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Clinical Policy Bulletin:
Aerosolized or Irrigated Anti-infectives for Sinusitis
Number: 0593


Policy

Aetna considers nasally aerosolized or irrigated anti-infectives experimental and investigational for the treatment of sinusitis and other indications because there is inadequate published clinical evidence of the effectiveness of this approach.

See also CPB 0065 - Nebulizers.



Background

The SinuNEB (SinusPharmacy) is a device that nebulizes antibiotics, anti-fungals, and medications for the treatment of sinusitis.  According to the manufacturer of the SinuNEB, administration of anti-infectives via nebulization directly to the lining of the sinuses results in a more rapid response, greater effectiveness, reduced re-infection, and fewer side effects than oral or intravenous anti-infective administration.  The brand name for the unique formulations used by SinusPharmacy in their treatment of sinusitis is AdhesENT.  These special formulations supposedly can increase the medication's adherence in the sinus cavities, and improve the effectiveness of the aerosolized treatment by allowing delivery to the disease site.

However, there are insufficient published clinical studies to support these claims.  SinusPharmacy (Scheinberg et al, 2002) reported on the results of an uncontrolled study of nebulized antibiotics 41 patients with sinusitis, reported an “excellent” or “good” outcome in 34 patients (82 %) after 3 to 6 weeks of treatment.  Vaughan and Carvahlo (2002) reported on a retrospective chart review of patients with chronic sinusitis who were treated with nebulized antibiotics.  The investigators reported clearing of the initial bacteria that the nebulized antibiotic was directed against in 28 patients, clearing of infection and a new infection with a different organism in 10 patients, clearing and re-infection with the same organism in 6 patients, and persistent infection in 6 patients.  Because these were not prospective, randomized studies, no firm conclusions about the effectiveness of nebulized antibiotics in sinusitis can be drawn from these studies.

Published randomized clinical studies of nebulized antibiotics found that nebulized antibiotics have no significant effect.  A randomized clinical study from Desrosiers et al (2001) involving 20 patients with chronic, refractory sinusitis found no clinically significant difference in effectiveness between nebulized tobramycin-saline solution and nebulized saline.  These results lead the authors to conclude that "addition of tobramycin [to saline nebulizer] appears to be of minimal benefit."

A pilot study by Videler et al (2008) found nebulized topical antibiotic therapy was no more effective in relieving sinusitis symptoms than saline-based placebo in patients with recalcitrant chronic rhinosinusitis.  The investigators reported on a randomized, placebo-controlled, double-blind, cross-over pilot study that was conducted in 14 patients with recalcitrant chronic rhinosinusitis.  Nasal irrigation with bacitracin/colimycin or placebo using the RhinoFlow nebulizer twice daily was administered in combination with oral levofloxacin.  Severity of a diversity of symptoms was measured using the visual analog score (VAS), a Disease-Specific Symptom Score and the SF-36 questionnaire. Nasal endoscopic findings were also assessed. The investigators reported that, for most VAS items and Disease-Specific Symptom Scores, a reduction in severity of symptoms was noted in both the bacitracin/colimycin and the placebo group.  No significant difference was found between the 2 arms (bacitracin/colimycin versus placebo).  Most SF-36 items improved, compared with the situation before treatment in both groups.  However, no significant difference was found between the verum and placebo arm.  Endoscopic findings did not reveal significant differences when comparing the 2 treatments.  The investigators concluded that the outcome of this study suggests a beneficial effect of nebulizing the nose with saline.  The investigators noted that this study again shows that adding antibiotics to local saline is not effective.  "Although the placebo-controlled studies looking at the effect of local antibiotics are all small they all point to the same direction: no effect. Definite conclusions however need a large randomized, multicenter study."

Anti-infectives have also been administered by nasal irrigation in sinusitis.  There is a lack of reliable clinical evidence of the effectiveness of nasally irrigated anti-infectives in sinusitis.

No published guidelines on sinusitis management from leading professional medical organizations discuss any role for nebulized or nasally irrigated antibiotics.  Thus, aerosolized or nasally irrigated anti-infectives are considered experimental and investigational for the treatment of sinusitis.

Hageman et al (2006) stated that although the theory behind aerosolized administration of antibiotics seems to be sound, there are limited available data to support the routine use of this modality.  Due to the gaps still existing in the knowledge base regarding the routine use of aerosolized antibiotics, caution should be exercised when attempting to administer antimicrobials via this route in situations falling outside clearly established indications such as the treatment of patients with cystic fibrosis or Pneumocystis pneumonia.

Laube (2007) noted that compared to research into aerosolized delivery of drugs to treat lung disease, research into nasal delivery of aerosolized drugs to treat sinusitis has been significantly neglected.  This is despite the fact that more people suffer from sinusitis than asthma in the United States, and its consequences result in considerable discomfort, lost work days, and money spent on health care.  A number of studies have shown that a high proportion of aerosolized medications delivered by metered dose inhalers and aqueous spray devices deposits in the anterior 1/3 of the nasal cavity.  However, the important targets for treating sinusitis lie beyond this region.  These include the middle meatus, the superior and posterior regions of the nasal cavity and the sinuses themselves.  The author examined the particle-related and device-related factors that are known to improve intra-nasal delivery of aerosolized medications to these targets and their effectiveness in patients with disease.  Based on this review, it is recommended that companies that are interested in improving aerosol delivery to treat sinusitis utilize both in vivo imaging modalities and in vitro models of the nasal cavity and sinuses to assess intra-nasal aerosol delivery and device performance during the development stage.  Once device design has been optimized, it is recommended that device manufacturers and pharmaceutical companies move beyond the current reliance on anecdotal reporting and uncontrolled trials to clinical studies that are randomized and placebo-controlled and that quantify changes both in symptoms and in functional parameters to determine drug effectiveness with their device.

Adappa et al (2012) reviewed the recent literature of nasal irrigations with or without drugs, including delivery systems, nasal saline, antibiotics, anti-fungals, steroids, surfactants, and interleukin (IL)-5 modulators, for the treatment of chronic rhino-sinusitis (CRS).  As antibiotic resistance increases in CRS, culture-directed, rather than empiric, topical antibiotics are increasingly critical in optimal treatment.  Topical irrigation with mupirocin significantly reduces Staphylococcus aureus biofilm mass in-vitro.  Surfactants and humanized anti-IL-5 monoclonal antibody are novel therapies demonstrating promising results in CRS.  The authors concluded that physiologic saline irrigation is beneficial in the treatment of symptoms of CRS.  Low-level evidence supports the effectiveness of topical antibiotics in the treatment of CRS.  The use of topical anti-fungals is not supported by the majority of studies.  Intra-nasal steroids are beneficial in the treatment of CRS with nasal polyposis.  There is insufficient evidence to demonstrate a clear overall benefit for topical steroids in CRS without nasal polyposis.

In a Cochrane review, Lemiengre et al (2012) evaluated the effect of antibiotics in adults with clinically diagnosed rhino-sinusitis in primary care settings.  These investigators searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2012), MEDLINE (January 1950 to February week 4, 2012) and EMBASE (January 1974 to February 2012).  Randomized controlled trials (RCTs) of antibiotics versus placebo in participants with rhinosinusitis-like signs or symptoms were selected for analysis.  Two authors independently extracted data and assessed the risk of bias.  They contacted trial authors for additional information, and collected information on adverse effects from the trials.  These researchers included 10 trials involving 2,450 participants.  Overall, the risk of bias in these studies was low.  Irrespective of the treatment group, 47 % of participants were cured after 1 week and 71 % after 14 days.  Antibiotics can shorten the time to cure, but only 5 more participants per 100 will cure faster at any time point between 7 and 14 days if they receive antibiotics instead of placebo (number needed to treat to benefit (NNTB)) 18 (95 % confidence interval (CI):  10 to 115, I(2) statistic 0 %, 8 trials).  Purulent secretion resolves faster with antibiotics (odds ratio (OR) 1.58 (95 % CI: 1.13 to 2.22)), (NNTB 11, 95 % CI: 6 to 51, I(2) statistic 0 %, 3 trials).  However, 27 % of the participants who received antibiotics and 15 % of those who received placebo experienced adverse events (OR 2.10, 95 % CI: 1.60 to 2.77) (number needed to treat to harm (NNTH)) 8 (95 % CI: 6 to 13, I(2) statistic 13 %, 7 trials).  More participants in the placebo group needed to start antibiotic therapy because of an abnormal course of rhino-sinusitis (OR 0.49, 95 % CI: 0.36 to 0.66), NNTH 20 (95 % CI: 14 to 35, I(2) statistic 0 %, 8 trials).  Only 1 disease-related complication (brain abscess) occurred in a patient treated with antibiotics.  The authors concluded that the potential benefit of antibiotics in the treatment of clinically diagnosed acute rhino-sinusitis needs to be seen in the context of a high prevalence of adverse events.  Taking into account antibiotic resistance and the very low incidence of serious complications, the authors concluded that there is no place for antibiotics for the patient with clinically diagnosed, uncomplicated acute rhino-sinusitis.  This review cannot make recommendations for children, patients with a suppressed immune system and patients with severe disease, as these populations were not included in the available trials.

In a meta-analysis, Sacks et al (2012) assessed the potential advantage of either topical or systemic anti-fungal therapy in the symptomatic treatment of CRS to aid physicians in making informed decisions about treating patients with CRS.  All studies obtained from searches were reviewed and trials meeting the eligibility criteria were selected.  Chronic rhino-sinusitis was defined using either the European Position Paper on Rhinosinusitis and Nasal Polyps or American Academy of Otolaryngology-Head and Neck Surgery criteria.  Authors were contacted and original data were used for data analysis.  A total of 5 studies investigating topical antifungals and 1 investigating systemic antifungals met the inclusion criteria.  All trials were double-blinded and randomized.  Pooled meta-analysis showed no statistically significant benefit of topical or systemic antifungals over placebo.  Symptoms scores statistically favored the placebo group for this outcome.  Adverse event reporting was higher in the anti-fungal group.  The authors concluded that reported side-effects of anti-fungal therapies may outweigh any potential benefits of treatment based on this meta-analysis and the authors therefore do not advocate the use anti-fungal treatment in the management of CRS.

 
CPT Codes / HCPCS Codes / ICD-9 Codes
Other CPT codes related to the CPB::
94664
99503
HCPCS codes not covered for indications listed in the CPB::
E0574 Ultrasonic/electronic aerosol generator with small volume nebulizer
E0575 Nebulizer, ultrasonic, large volume
E0580 Nebulizer, durable, glass or autoclavable plastic, bottle type, for use with regulator or flowmeter
E0585 Nebulizer, with compressor and heater
Other HCPCS codes related to the CPB::
A7013 Filter, disposable, used with aerosol compressor or ultrasonic generator
A7014 Filter, non-disposable, used with aerosol compressor or ultrasonic generator
A7015 Aerosol mask, used with DME nebulizer
E0572 Aerosol compressor, adjustable pressure, light duty for intermittent use
ICD-9 codes not covered for indications listed in the CPB::
461.0 - 461.9 Acute sinusitis
473.0 - 473.9 Chronic sinusitis


The above policy is based on the following references:
  1. American Academy of Pediatrics. Subcommittee on Management of Sinusitis and Committee on Quality Improvement. Clinical Practice Guideline: Management of sinusitis. Pediatrics. 2001;108(3):798-808.
  2. Snow V, Mottur-Pilson C, Hickner JM; American Academy of Family Physicians; American College of Physicians-American Society of Internal Medicine; Centers for Disease Control; Infectious Diseases Society of America. Principles of appropriate antibiotic use for acute sinusitis in adults. Ann Intern Med. 2001;134(6):495-497.
  3. Spector SL, Bernstein IL, Li JT, et al. Parameters for the diagnosis and management of sinusitis. Ann Allergy Asthma Immunol. 1998;102(6 Pt 2):S107-S144.
  4. University of Michigan Health System. Acute rhinosinusitis in adults. Ann Arbor, MI: University of Michigan Health System; December 1999.
  5. Institute for Clinical Systems Improvement. Acute sinusitis in adults. ICSI health care guidelines; no. GRD02. Bloomington, MN: Institute for Clinical Systems Improvement (ICSI); December 1999.
  6. Institute for Clinical Systems Improvement. Rhinitis. Bloomington, MN: Institute for Clinical Systems Improvement (ICSI); June 2000.
  7. Agency for Healthcare Research and Quality (AHRQ). Diagnosis and treatment of acute bacterial rhinosinusitis. Evidence Report/Technology Assessment Number 9. AHCPR Publication No. 99-E016. Rockville, MD: AHRQ, 1999.
  8. Brooks I, Gooch WM 3rd, Jenkins SG, et al. Medical management of acute bacterial sinusitis. Recommendations of a clinical advisory committee on pediatric and adult sinusitis. Ann Otol Rhinol Laryngol Suppl. 2000;182:2-20.
  9. Ressel G. Principles of appropriate antibiotic use: Part III. Acute rhinosinusitis. Centers for Disease Control and Prevention. Am Fam Physician. 2001;64(4):685-686.
  10. Sinus and Allergy Health Partnership. Antimicrobial treatment guidelines for acute bacterial rhinosinusitis. Otolaryngol Head Neck Surg. 2000;123(1 Pt 2):5-31.
  11. SinusPharmacy. SinuNEB. Carpinteria, CA: SinusPharmacy Inc.; 2001. Available at: http://www.sinuneb.com. Accessed January 15, 2002.
  12. Scheinberg PA, Otsuhi A. Nebulized antibiotics for the treatment of acute exacerbations of chronic rhinosinusitis. Ear Nose Throat J. 2002;81(9):648-652.
  13. Desrosiers MY, Salas-Prato M. Treatment of chronic rhinosinusitis refractory to other treatments with topical antibiotic therapy delivered by means of a large-particle nebulizer: Results of a controlled trial. Otolaryngol Head Neck Surg. 2001;125(3):265-269.
  14. Vaughan WC. Nebulization of antibiotics in management of sinusitis. Curr Infect Dis Rep. 2004;6(3):187-190.
  15. Wahl KJ, Otsuji A. New medical management techniques for acute exacerbations of chronic rhinosinusitis. Curr Opin Otolaryngol Head Neck Surg. 2003;11(1):27-32.
  16. Vaughan WC, Carvalho G. Use of nebulized antibiotics for acute infections in chronic sinusitis. Otolaryngol Head Neck Surg. 2002;127(6):558-568.
  17. Klepser ME. Role of nebulized antibiotics for the treatment of respiratory infections. Curr Opin Infect Dis. 2004;17(2):109-112.
  18. American Academy of Pediatrics. Subcommittee on Management of Sinusitis and Committee on Quality Improvement. Clinical practice guideline: Management of sinusitis. Pediatrics. 2001;108(3):798-808.
  19. Slavin RG, Spector SL, Bernstein IL, et al. The diagnosis and management of sinusitis: A practice parameter update. J Allergy Clin Immunol. 2005;116(6 Suppl):S13-S47.
  20. Hagerman JK, Hancock KE, Klepser ME. Aerosolised antibiotics: A critical appraisal of their use. Expert Opin Drug Deliv. 2006;3(1):71-86.
  21. Laube BL. Devices for aerosol delivery to treat sinusitis. J Aerosol Med. 2007;20 Suppl 1:S5-S17; discussion S17-S18.
  22. Dubin MG, Liu C, Lin SY, Senior BA. American Rhinologic Society member survey on 'maximal medical therapy' for chronic rhinosinusitis. Am J Rhinol. 2007;21(4):483-488.
  23. Videler WJ, van Drunen CM, Reitsma JB, Fokkens WJ. Nebulized bacitracin/colimycin: A treatment option in recalcitrant chronic rhinosinusitis with Staphylococcus aureus? A double-blind, randomized, placebo-controlled, cross-over pilot study. Rhinology. 2008;46(2):92-98.
  24. Moeller W, Schuschnig U, Meyer G, et al. Ventilation and aerosolized drug delivery to the paranasal sinuses using pulsating airflow - a preliminary study. Rhinology. 2009;47(4):405-412.
  25. Adappa ND, Wei CC, Palmer JN. Nasal irrigation with or without drugs: The evidence. Curr Opin Otolaryngol Head Neck Surg. 2012;20(1):53-57.
  26. Lemiengre MB, van Driel ML, Merenstein D, et al. Antibiotics for clinically diagnosed acute rhinosinusitis in adults. Cochrane Database Syst Rev. 2012;10:CD006089.
  27. Sacks PL 4th, Harvey RJ, Rimmer J, et al. Antifungal therapy in the treatment of chronic rhinosinusitis: A meta-analysis. Am J Rhinol Allergy. 2012;26(2):141-147.


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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.
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