Inhaled Antibiotic Therapy for the Treatment of Upper Respiratory Tract Infections

Abstract

Upper respiratory tract infections (URTIs), primarily acute rhinopharyngitis, tonsillitis, adenoiditis, and rhinosinusitis (RS), are major causes of morbidity in both children and adults of any age. In addition to the frequent occurrence of related medical problems and the associated socioeconomic costs, URTIs have a significant impact on the quality of life of patients and their families, and have placed an escalating financial burden on the global healthcare system. Most URTIs are caused by viruses and require only symptomatic treatment. However, a number of cases, particularly those that are severe, recurrent, or chronic, have a bacterial etiology and need appropriate antimicrobial treatment to avoid complications or frequent exacerbations. To ensure therapeutic antibiotic concentration without any significant systemic drug exposure, the direct delivery of antibiotics to the upper respiratory tract by inhalation is a potential solution. The main aim of this review is to determine if and when aerosolized antibiotics can be effectively used to treat URTIs in noncystic fibrosis (non-CF) patients. There is a lack of strong evidence for the use of nebulized antibiotics to treat URTIs in non-CF patients. The only disease for which positive results have been reported is chronic RS in adults. However, conflicting conclusions have been drawn, and many problems related to the drug of choice, dosages, duration of treatment, and the best device for administration remain unsolved. Further studies are needed to better determine when and through which treatment modalities inhaled antibiotics can positively modify the course of chronic RS.

Introduction

Upper respiratory tract infections (URTIs), primarily acute rhinopharyngitis (RF), tonsillitis, adenoiditis, and rhinosinusitis (RS), are major causes of morbidity in both children and adults of any age.^(1,2) In addition to the frequent occurrence of related medical problems and the associated socioeconomic costs, URTIs have a significant impact on the quality of life of patients and their families, and have placed an escalating financial burden on the global healthcare system.^(1,2) Most URTIs are caused by viruses and require only symptomatic treatment. However, a number of cases, particularly those that are severe, recurrent, or chronic, have a bacterial etiology and need appropriate antimicrobial treatment to avoid complications or frequent exacerbations.^(3–5) Typically, antibiotics are given by mouth or intravenously. However, the systemic use of these drugs is frequently accompanied by the development of related adverse events that can significantly worsen a patient's clinical condition, increase disease duration, require further therapies, and increase costs. Moreover, systemic administration can be ineffective because the drugs used for treatment, owing to their pharmacokinetics and pharmacodynamics, may reach suboptimal concentrations at the site of infection. Consequently, eradication of infecting pathogens is not possible, and the selection of resistant bacterial strains may occur.⁽⁶⁾ The direct delivery of antibiotics to the upper respiratory tract through inhalation may be able to overcome these limitations and ensure that therapeutic antibiotic concentrations are delivered without any significant systemic drug exposure.

Inhaled antibiotics have long been used to treat patients with cystic fibrosis (CF) and have produced very good results with a marginal incidence of adverse events.^(7,8) The success of aerosol antibiotics in CF has led to the consideration of similar therapies for patients with other chronic airway infections such as non-CF, bronchiectasis, tuberculosis, nontuberculous mycobacteria infection, Pneumocystis jiroveci infection, and ventilator-associated pneumonia.⁽⁹⁾ Recently, the use of inhaled antibiotics to treat URTIs has been examined. However, the available data are limited, and there are conflicting results. The main aim of this review is to determine if and when aerosolized antibiotics can be effectively used to treat URTIs in non-CF patients.

Problems with the Use of Aerosolized Antibiotics

In cases of recurrent and chronic URTIs, gram-negative bacteria, S. aureus, anaerobes, or fungi are the main etiologic agents.^(10–14) Cephalosporins or specific antistaphylococcal drugs have been used to treat infections caused by S. aureus, anaerobes, and gram-negative pathogens.⁽¹⁵⁾ However, none of these drugs is licensed for use through inhalation.

Another problem regarding the use of aerosolized antibiotics for URTIs is the lack of studies regarding the safety of potentially inhalable antibiotics, especially when protracted administration is suggested such as in chronic URTIs. Presently, licensed preparations have been extensively studied in CF patients and were found to be generally safe and acceptably tolerated.⁽¹⁶⁾ However, studies specifically planned to evaluate the safety and tolerability of these antibiotics for URTI treatment in non-CF patients are needed.

Oropharyngeal deposition increases once the particle size is more than 10 μm.⁽¹⁷⁾ Devices commonly used to treat URTIs generate droplets between 50 and 100 μm. These relatively large droplets remain in the upper respiratory tract and do not reach the lungs, and thus exerting their activity only where it is required, with marginal lung inhalation.^(18–20) In the majority of studies involving URTI patients, nebulized drug particles with a median mass aerodynamic diameter greater than 10 μm were used. However, devices used to treat nasopharyngeal diseases are not effective in RS patients because penetration into the paranasal sinuses is only possible with smaller droplets. Consequently, the best choice of device for URTI patients is strictly related to the type of disease being treated. Devices that produce larger droplets are potentially useful for the treatment of RF, tonsillitis, and adenoiditis only.

Inhaled Antibiotic Therapy for Acute RF, Recurrent Tonsillitis, and Adenoiditis

Table 1 summarizes the main studies on inhaled antibiotic therapy for acute RF, recurrent tonsillitis, and adenoiditis.

Table 1.

Main Studies on Inhaled Antibiotic Therapy for Acute RF, Recurrent Tonsillitis, and Adenoiditis

Authors	Study population	Treatment	Main findings
Varricchio et al.⁽²²⁾	Children (n = 357), aged 3–6 years, with acute bacterial RF	Treated with 15 mg of aerosolized tobramycin (group A) or 50 mg/kg of amoxicillin/clavulanate (group B) twice daily for 10 days	Inhaled tobramycin induced a better improvement in nasal obstruction (p < 0.05), adenoidal hypertrophy (p < 0.01), tympanic inflammation (p < 0.01), rhinomanometry (p < 0.01), and cultures (p < 0.05); no safety issue
Varricchio et al.⁽²³⁾	Children (n = 90), aged 3–6 years, with acute bacterial RF	Treated with aerosolized thiamphenicol associated with acetylcysteine (250 mg: 1/2 vial in the morning and 1/2 vial in the evening; group A) or saline solution twice daily (group B), both of them for 5 days. Both treatments were administered using Rinowash as device	Actively treated children showed a significant improvement in nasal obstruction (p < 0.05), mucopurulent rhinorrhea (p < 0.05), postnasal drip (p < 0.05), cough (p < 0.05), sore throat (p < 0.05), fever (p < 0.05), and cultures (p < 0.05); no safety issue
Macchi et al.⁽²⁵⁾	Children (n = 204), aged 1–12 years, with chronic adenotonsillitis who had been listed for surgery due to obstructive symptoms and recurrent acute infections	Randomized to treatment with thiamphenicol glycinate acetylcysteinate, dosage 250 mg/day in two administrations plus beclomethasone with a dosage of 400 microg/day in two administrations or no treatment control group. The drugs were administered by aerosol for 10 days/month over a period of 6 months	Aerosol treatment with thiamphenicol glycinate acetylcysteinate plus beclomethasone resulted in a significantly lower proportion of patients requiring surgery (29 of 101; 29%) compared to patients in the control group (100 of 103; 97%, p < 0.0001). Treatment was also associated with a reduction of nasal obstruction and a decrease in the number of infectious episodes; no treatment-related adverse event

RF, rhinopharyngitis.

RF is one of the diseases for which physicians are most frequently consulted.^(1,2) The vast majority of RF cases have a viral etiology. However, some viral RF cases exhibit complications such as a superimposed bacterial infection that leads to severe and persistent purulent rhinorrhea.⁽²¹⁾ Inhaled antibiotics have been considered as a possible solution for these complications owing to the avoidance of systemic antimicrobial drug effects on intestinal flora and a reduction in the risk of systemic adverse events. A randomized, double-blind study by Varricchio et al. was the first attempt at confirming this hypothesis.⁽²²⁾ These authors enrolled 311 children with a median age of 4.5 years. The participants were divided into two homogenous groups that received either 15 mg of aerosolized tobramycin or 50 mg/kg/day of oral amoxicillin–clavulanate. For all patients, a nasal swab, a clinical evaluation, fiberoptic endoscopy, tympanometry, and rhinomanometry were completed at baseline and after 10 days of treatment. Although both treatments were effective at resolving acute RF, the topical tobramycin produced a significantly higher improvement in clinical and functional parameters such as nasal obstruction (p < 0.05), adenoid hypertrophy (p < 0.01), tympanic inflammation (p < 0.01), rhinomanometry findings (p < 0.01), and cultures (p < 0.05); moreover, inhaled tobramycin was well tolerated and resulted in good compliance.

Another study conducted by the same authors involved 94 children with a median age of 3.7 years and documented acute bacterial RF.⁽²³⁾ The patients were divided into two homogeneous groups that received either thiamphenicol with acetylcysteine or a hypertonic solution through nasal douche for 5 days. Both treatments were well tolerated and showed a similar compliance rate. However, only children receiving tobramycin showed a significant reduction in rhinorrhea, postnasal drip, nasal obstruction, cough, sore throat, fever, and positive cultures.

These results are encouraging, but the study population was quite limited, and further studies on larger samples are needed before the use of aerosolized antibiotics can be recommended to treat acute RF. Moreover, available data from children cannot be extrapolated to adults. Acute RF is mainly a viral disease, and the presence of bacteria in a nasal swab is not indicative of a true bacterial infection because many respiratory pathogens can be present with no role in the disease progression.⁽²⁴⁾ Both studies by Varricchio et al. had some methodological limitations owing to the lack of accurate microbiological data collection. The infecting bacteria were not always identified and their sensitivity to the drug treatments was not defined. Moreover, the follow-up was limited to the study period, and no evaluation of possible relapse or recurrence was made.

Similar conclusions can be drawn regarding the use of aerosolized antibiotics in children with recurrent acute tonsillitis and adenoiditis. Macchi et al. evaluated the aerosol administration of thiamphenicol-acetylcysteine (TGA) and beclomethasone in children with recurrent acute tonsillitis and adenoiditis who were previously scheduled for tonsillectomy and/or adenoidectomy.⁽²⁵⁾ The study sought to determine if aerosol therapy could delay or prevent surgery. A total of 204 children with a median age of 5.6 years were randomized into two groups. One group received treatment with TGA and beclomethasone administered by aerosol for 10 days/month over a period of 6 months, and the second group served as an untreated control group. All of the children underwent follow-up for 1 year. Only 29% of treated children required surgery over the course of the study, whereas 97% of the children in the control group underwent surgery.

Children who received aerosol therapy showed a significant reduction in nasal obstruction and the number of infectious episodes during the 6-month treatment period and during the 6 months after treatment cessation compared with the placebo group. The combined treatment using TGA and beclomethasone was well tolerated, and no severe adverse events were reported; thus, the authors suggested that this long-lasting treatment could be used to reduce the need for surgery in children with recurrent acute tonsillitis and adenoiditis.⁽²⁵⁾ However, this conclusion seems debatable because the study had methodological problems due to the heterogenous characteristics of the study population, and the antibiotic was administered in conjunction with other drugs. In particular, acetylcysteine is a medication commonly used for its mucolytic properties in the treatment of CF and has been demonstrated to reduce the adhesion of respiratory pathogens to epithelial cells and inhibit bacterial biofilm production,^(26–28) without affecting the antibacterial activity of thiamphenicol.⁽²⁹⁾

The nasopharynx and its surrounding tissues are important reservoirs of resistant and sometimes polymicrobial bacterial biofilms, which could play a key role in the recurrence of URTIs. Biofilms have been shown to cover the adenoidal surface of children suffering from recurrent otitis media.^(30,31) A prevalent gram-positive bacterial biofilm was found more frequently in the tonsils of children with chronic tonsillitis than in children with tonsil hypertrophy, but no recurrent infections.⁽³²⁾ Moreover, the presence of polymicrobial bacterial biofilms has been associated with recurrent or recalcitrant paranasal sinus infections in adults⁽³³⁾ and a poorer response to both medical and surgical treatment.^(34,35) Consequently, elimination or reduction of biofilms through the use of acetylcysteine may have significantly reduced the risk of infectious episodes and thus favoring the antibacterial activity of the inhaled antibiotic.

Inhaled Antibiotic Therapy for RS

Table 2 showed the main systematic reviews on inhaled antibiotic therapy for RS.

Table 2.

Main Systematic Reviews on Inhaled Antibiotic Therapy for RS

Authors	Methods	Results	Conclusions
Lim et al.⁽⁴¹⁾	Systematic review of literature from December 1, 1949 to September 30, 2007	Only one of the randomized studies showed a positive outcome. Overall, there was low-level corroborative evidence for the use of antibacterials. No definite conclusions could be made regarding the use of antifungals. Both stable and acute exacerbations of chronic RS appeared to benefit from topical antimicrobials	Topical antibiotics appear effective in the management of chronic RS. Given the combination of low-level evidence, topical antibiotics should not be first-line management, but may be attempted in patients refractory to the traditional topical steroids and oral antibiotics
Rudmik et al.⁽⁴²⁾	Systematic review of the literature related to adult population >18 years old with chronic RS	This review identified and evaluated the literature on five topical therapy strategies for chronic RS as follows: saline irrigation, topical steroid, topical antibiotic, topical antifungal, and topical alternatives (surfactant, manuka honey, and xylitol irrigations)	Sinonasal saline irrigation and standard topical nasal steroid therapy are recommended in the topical treatment of chronic RS. Nonstandard (off-label) topical sinonasal steroid therapies can be an option. The evidence recommends against the use of topical antifungal therapy and topical antibiotic therapy delivered using nebulization and spray techniques in routine cases. There is insufficient clinical research to provide recommendations for alternative therapies or topical antibiotic therapy delivered using other delivery methods (e.g., irrigations)
Woodhouse et al.⁽⁴⁵⁾	Systematic review of publications up to February 2011	The four trials analyzing the effectiveness of nebulized antibiotics for refractory chronic RS in adults were diverse in their methods, and different antibiotics were used in each trial. Furthermore, all of the trials had small sample sizes, with the largest comprising 42 patients. Two trials with no control groups found that nebulized antibiotics led to an improvement in symptoms. Nebulized antibiotics were well tolerated, with only minor adverse effects noted	Use of nebulized antibiotics for refractory chronic RS cannot be recommended. Although supportive evidence is limited, nebulized antibiotics appear to improve RS symptoms in some patients with minimal adverse effects

RS, rhinopharyngitis.

Systemic antibiotic therapy represents the first-line treatment for subacute and chronic RS. For acute cases, systematic treatments are debated because most of the mild cases tend to resolve spontaneously.^(36,37) Various topical treatment options have been evaluated as a possible support therapy for RS such as nasal irrigation and topical nasal corticosteroid administration.^(38–40) In addition, aerosolized antibiotics have been widely used as a treatment for RS. The use of topical antibiotics for RS has been extensively studied. The majority of the studies have focused on chronic cases and patients previously treated with surgical interventions. Despite the plethora of data, there are conflicting conclusions about the real impact of this treatment on the final outcome of RS and its use remains a subject of debate.

In their 2008 review, Lim et al. examined the available evidence for topical antimicrobials used to treat chronic RS and its complications. These authors reported higher efficacy in treatments using antibacterial agents compared to antifungal agents.⁽⁴¹⁾ With regard to the delivery methods used for topical treatment, the authors found no evidence to support the use of antibiotics delivered as nasal spray, while they found some low-level evidence for antimicrobial nebulization. The higher efficacy of nebulized antimicrobials may be due a lack of dependence on mucociliary clearance for drug distribution and a wider distribution surface for the administered drug.⁽⁴¹⁾

In contrast, a recent literature review by Rudmik et al. concluded that the currently available evidence recommends against the use of nebulized antibiotics and spray-administered antibiotics for the routine treatment of chronic RS.⁽⁴²⁾ The differences in the efficacy of inhaled antibiotics among studies could depend on several factors, including the type of drug used, the drug dosage and length of administration, the characteristics of the causative agent, and the severity of disease. However, the most important problem resides in the sinuses themselves. Even under healthy conditions, the sinuses are poorly ventilated, and they can become further excluded from ventilation in cases of disease-induced edema of the ostial mucosa.⁽²⁾ Nebulized drugs are inefficient at depositing into the paranasal sinuses and can reach the site of the infection only when droplets are <5 μm, a size nearly identical to that used for lung diseases.⁽⁴¹⁾ The method used to administer the antibiotics, previous surgical intervention, and enlargement of the meatal ostia may favor the accumulation of antibiotics in the sinuses.

Recently, a pulsating aerosol delivery technique has been studied as an option to improve inhaled drug distribution to the paranasal sinuses. Studies in nasal casts and healthy volunteers have shown that up to 8% of the nasally deposited drug can deposit within the sinuses, whereas this cannot be achieved using nasal pump sprays.⁽⁴³⁾ In addition, the retention kinetics of the radiolabel deposited in the nose was prolonged when compared with nasal pump sprays. Moreover, Möller et al. compared the deposition distribution of pulsating aerosols in patients with chronic RS before and after surgical treatment.⁽⁴⁴⁾ Before surgery, 2.7% ± 1.4% of the nasally administered dose was detected in the maxillary and sphenoidal sinuses. Re-evaluation at 143 ± 48 days after surgery showed that ∼4% of the nasally administered dose was found in the paranasal sinuses. However, frontal sinus deposition of the pulsating aerosol was below the detection limit before and after the endoscopic sinus surgery.

Together with the lack of conclusive data regarding the efficacy of inhaled antibiotics in the treatment of RS, various other issues regarding the use of topical antibiotics in the treatment of this disease are still unanswered and should be addressed in future studies. The lack of data regarding the possible superiority of inhaled antibiotics in terms of decreased costs and reduced adverse events (such as nebulized saline solution) when compared with other therapeutic methods deserves attention. In a 2011 meta-analysis, Woodhouse and Cleveland reported that both nebulized saline irrigation and nebulized antibiotics significantly improved the symptoms of patients suffering from chronic RS⁽⁴⁵⁾; however, the superiority of topical antibiotic therapies has not been assessed.⁽⁴⁰⁾ In a systematic review, Lim et al. analyzed 14 high-level studies conducted in patients with chronic RS and found that topical antibiotic therapies produced a better outcome when compared with nasal saline irrigation in only one of the evaluated studies.⁽⁴¹⁾ Further clinical trials are needed to better assess the safety profile of each inhalation therapy and determine the dose and length of treatment that minimizes the risk of systemic adverse events.

Conclusions

In contrast to the results in CF patients, there is no strong evidence to support the use of nebulized antibiotics for the treatment of URTIs. The only disease for which favorable data have been collected is chronic RS in adults. However, there are conflicting conclusions, and many problems related to the drug of choice, dosages, duration of treatment, and the best device for administration remain unsolved. Further studies are needed to better define the conditions, in which inhaled antibiotics can positively modify the course of chronic RS. Regarding the use of inhaled antibiotics for other URTIs, primarily acute RF, recurrent tonsillitis, and adenoiditis, a lack of reliable findings prevents any firm conclusions. On the contrary, these diseases are frequently mild clinical conditions that can be efficiently treated with many approaches that are effective, less expensive, and simpler to use.

Footnotes

Acknowledgment

This review was supported by grants from the Italian Ministry of Health (Progetto a concorso 850/03 2015–2016 and Progetto ricerca corrente 2016 850/01).

Author Disclosure Statement

No competing financial interests exist.

References

Chiappini

, Mazzantini

, Bruzzese

, Capuano

, Colombo

, Cricelli

, Di Mauro

, Esposito

, Festini

, Guarino

, Miniello

, Principi

, Marchisio

, Rafaniello

, Rossi

, Sportiello

, Tancredi

, Venturini

, Galli

, and de Martino

: Rational use of antibiotics for the management of children's respiratory tract infections in the ambulatory setting: an evidence—based consensus by the Italian Society of Preventive and Social Pediatrics. Paediatr Respir Rev. 2014; 15:231–236.

Harris

, Hicks

, and Qaseem

: Appropriate antibiotic use for acute respiratory tract infection in adults: advice for high-value care from the American College of Physicians and the Centers for Disease Control and Prevention. Ann Intern Med. 2016; Epub Jan 19. Doi:10.7326/M15-1840.

Brook

: Microbial dynamics of purulent nasopharyngitis in children. Int J Pediatr Otorhinolaryngol. 2003; 67:1047–1053.

Smith

, Ference

, Evans

, Tan

, Kern

, and Chandra

: The prevalence of bacterial infection in acute rhinosinusitis: a systematic review and meta-analysis. Laryngoscope. 2015; 125:57–69.

McKerrow

: Recurrent tonsillitis. Clin Evid. 2002; 7:477–480.

LiPuma

: Microbiological and immunologic considerations with aerosolized drug delivery. Chest. 2001; 120:118S–123S.

Tay

, Reid

, and Bell

: Inhaled antibiotics in cystic fibrosis (CF) and non-CF bronchiectasis. Semin Respir Crit Care Med. 2015; 36:267–286.

Vázquez-Espinosa

, Girón

, Gómez-Punter

, García-Castillo

, Valenzuela

, Cisneros

, Zamora

, García-Pérez

, and Ancochea

: Long-term safety and efficacy of tobramycin in the management of cystic fibrosis. J Ther Clin Risk Manag. 2015; 11:407–415.

Flume

, and Van Devanter

: Clinical applications of pulmonary delivery of antibiotics. Adv Drug Deliv Rev. 2015; 85:1–6.

10.

Brook

: Acute sinusitis in children. Pediatr Clin North Am. 2013; 60:409–424.

11.

Esposito

, Marchisio

, Tenconi

, Tagliaferri

, Albertario

, Patria

, and Principi

: Diagnosis of acute rhinosinusitis. Pediatr Allergy Immunol. 2012; 23 Suppl. 22:17–19.

12.

Velkov

, Abdul Rahim

, Zhou

, Chan

, and Li

: Inhaled anti-infective chemotherapy for respiratory tract infections: successes, challenges and the road ahead. Adv Drug Deliv Rev. 2015; 85:65–82.

13.

Fuglesang

, and Bergan

: Chloramphenicol and thiamphenicol. Antibiot Chemother. 1982; 31:1–21.

14.

Ramakrishnan

, Hauser

, Feazel

, Ir

, Robertson

, and Frank

: Sinus microbiota varies among chronic rhinosinusitis phenotypes and predicts surgical outcome. J Allergy Clin Immunol. 2015; 136:334–342.

15.

Lim Lim

, Citardi

, and Leong

: Topical antimicrobials in the management of chronic rhinosinusitis: a systematic review. Am J Rhinol. 2008; 22:381–389.

16.

Zhou

, Tang

, Leung

, Chan

, and Chan

: Emerging inhalation aerosol devices and strategies: where are we headed?. Adv Drug Deliv Rev. 2014; 75:3–17.

17.

Myers

: The science guiding selection of an aerosol delivery device. Respir Care. 2013; 58:1963–1973.

18.

Djupesland

: Nasal drug delivery devices: characteristics and performance in a clinical perspective—a review. Drug Deliv Transl Res. 2013; 3:42–62.

19.

Vidgren

, and Kublik

: Nasal delivery systems and their effect on deposition and absorption. Adv Drug Deliv Rev. 1998; 29:157–177.

20.

Phipps

, and Gonda

: Droplets produced by medical nebulizers. Some factors affecting their size and solute concentration. Chest. 1990; 97:1327–1332.

21.

Windfuhr

, Toepfner

, Steffen

, Waldfahrer

, and Berner

: Clinical practice guideline: tonsillitis I. Diagnostics and nonsurgical management. Eur Arch Otorhinolaryngol. 2016; 273:989–1009.

22.

Varricchio

, Tricarico

, De Lucia

, Utili

, Tripodi

, Miraglia Del Giudice

, Capasso

, Sabatino

, Sgarrella

, Marseglia

, and Ciprandi

: Inhaled tobramycin in children with acute bacterial rhinopharyngitis. Int J Immunopathol Pharmacol. 2006; 19:131–140.

23.

Varricchio

, Capasso

, Di Gioacchino

, and Ciprandi

: Inhaled thiamphenicol and acetilcysteine in children with acute bacterial rhinopharyngitis. Int J Immunopathol Pharmacol. 2008; 21:625–629.

24.

García-Rodríguez

, and Fresnadillo Martínez

: Dynamics of nasopharyngeal colonization by potential respiratory pathogens. J Antimicrob Chemother. 2002; 50 Suppl S2:59–73.

25.

Macchi

, and Castelnuovo

: Aerosol antibiotic therapy in children with chronic upper airway infections: a potential alternative to surgery. Int J Immunopathol Pharmacol. 2009; 22:303–310.

26.

Riise

, Qvarfordt

, Larsson

, Eliasson

, and Andersson

: Inhibitory effect of N-acetylcysteine on adherence of Streptococcus pneumoniae and Haemophilus influenzae to human oropharyngeal epithelial cells in vitro. Respiration. 2000; 67:552–558.

27.

Olofsson

, Hermansson

, and Elwing

: N-acetyl-L-cysteine affects growth, extracellular polysaccharide production, and bacterial biofilm formation on solid surfaces. Appl Environ Microbiol. 2003; 69:4814–4822.

28.

Zhao

, and Liu

: N-acetylcysteine inhibits biofilms produced by Pseudomonas aeruginosa. BMC Microbiol. 2010; 10:140.

29.

Albini

, Belluco

, Berton

, Schioppacassi

, and Ungheri

: In vitro antibacterial activity of thiamphenicol glycinate acetylcysteinate against respiratory pathogens. Arzneimittelforschung. 1999; 49:533–537.

30.

Zuliani

, Carlisle

, Duberstein

, Haupert

, Syamal

, Berk

, Du

, and Coticchia

: Biofilm density in the pediatric nasopharynx: recurrent acute otitis media versus obstructive sleep apnea. Ann Otol Rhinol Laryngol. 2009; 118:519–524.

31.

Nistico

, Kreft

, Gieseke

, Coticchia

, Burrows

, Khampang

, Liu

, Kerschner

, Post

, Lonergan

, Sampath

, Hu

, Ehrlich

, Stoodley

, and Hall-Stoodley

: Adenoid reservoir for pathogenic biofilm bacteria. J Clin Microbiol. 2011; 49:1411–1420.

32.

Al-Mazrou

, and Al-Khattaf

: Adherent biofilms in adenotonsillar diseases in children. Arch Otolaryngol Head Neck Surg. 2008; 134:20–23.

33.

, Wang

, Sun

, Hu

, Yu

, and Wang

: Relationship between bacterial biofilm and clinical features of patients with chronic rhinosinusitis. Eur Arch Otorhinolaryngol. 2012; 269:155–163.

34.

Nazzari

, Torretta

, Pignataro

, Marchisio

, and Esposito

: Role of biofilm in children with recurrent upper respiratory tract infections. Eur J Clin Microbiol Infect Dis. 2015; 34:421–429.

35.

Zuliani

, Carron

, Gurrola

, Coleman

, Haupert

, Berk

, and Coticchia

: Identification of adenoid biofilms in chronic rhinosinusitis. Int J Pediatr Otorhinolaryngol. 2006; 70:1613–1617.

36.

Esposito

, and Principi

: Rhinosinusitis management in pediatrics: an overview. Int J Immunopathol Pharmacol. 2010; 23(1 Suppl.):53–55.

37.

Rosenfeld

, Piccirillo

, Chandrasekhar

, Brook

, Kumar

, Kramper

, Orlandi

, Palmer

, Patel

, Peters

, Walsh

, and Corrigan

: Clinical practice guideline (update): adult sinusitis executive summary. Otolaryngol Head Neck Surg. 2015; 152:598–609.

38.

Huang

, and Govindaraj

: Topical therapy in the management of chronic rhinosinusitis. Curr Opin Otolaryngol Head Neck Surg. 2013; 21:31–38.

39.

Fiocchi

, Sarratud

, Bouygue

, Ghiglioni

, Bernardo

, and Terracciano

: Topical treatment of rhinosinusitis. Pediatr Allergy Immunol. 2007; 18 Suppl. 18:62–67.

40.

Brietzke

, Shin

, Choi

, Lee

, Parikh

, Pena

, Prager

, Ramadan

, Veling

, Corrigan

, and Rosenfeld

: Clinical consensus statement: pediatric chronic rhinosinusitis. Otolaryngol Head Neck Surg. 2014; 151:542–553.

41.

Lim

, Citardi

, and Leong

: Topical antimicrobials in the management of chronic rhinosinusitis: a systematic review. Am J Rhinol. 2008; 22:381–389.

42.

Rudmik

, Hoy

, Schlosser

, Harvey

, Welch

, Lund

, and Smith

: Topical therapies in the management of chronic rhinosinusitis: an evidence-based review with recommendations. Int Forum Allergy Rhinol. 2013; 3:281–298.

43.

Möller

, Lübbers

, Münzing

, and Canis

: Pulsating airflow and drug delivery to paranasal sinuses. Curr Opin Otolaryngol Head Neck Surg. 2011; 19:48–53.

44.

Möller

, Schuschnig

, Bartenstein

, Meyer

, Häussinger

, Schmid

, and Becker

: Drug delivery to paranasal sinuses using pulsating aerosols. J Aerosol Med Pulm Drug Deliv. 2014; 27:255–263.

45.

Woodhouse

, and Cleveland

: Nebulized antibiotics for the treatment of refractory bacterial chronic rhinosinusitis. Ann Pharmacother. 2011; 45:798–802.