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.

Ventilator-Associated Pneumonia

In a meta-analysis and systematic review, Valachis et al (2015) evaluated the safety and effectiveness of aerosolized colistin as adjunctive therapy to intravenous (iv) anti-microbials or as monotherapy in the treatment of ventilator-associated pneumonia. The databases of Medline and Cochrane Library up to June 2013 and all reference lists of the included studies and relevant reviews were searched.  Studies were eligible if the safety and effectiveness of aerosolized colistin in the treatment of ventilator-associated pneumonia was evaluated.  An overall effect estimate for all dichotomous data as an OR with 95 % CI was calculated by the Mantel-Haenszel or the DerSimonian and Laird method depending on the statistical heterogeneity.  The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to interpret the findings. A total of 16 studies fulfilled the inclusion criteria: 8 were comparing adjunctive aerosolized versus iv colistin (7 observational cohort or case-control studies and 1 randomized trial) and were meta-analyzed, and 8 were single-arm and were only systematically reviewed.  The GRADE approach showed limitations of the study design and presence of inconsistency in most of the outcomes, but no obvious indirectness or imprecision of results reporting.  Based on the above assessments, the quality of evidence presented for each outcome ranged from "very low" to "low".  A significant improvement in clinical response (OR, 1.57; 95 % CI: 1.14 to 2.15; p = 0.006; I2 = 37 %), microbiological eradication (OR, 1.61; 95 % CI: 1.11 to 2.35; p = 0.01; I2 = 0 %), and infection-related mortality (OR, 0.58; 95 % CI: 0.34 to 0.96; p = 0.04; I2 = 46 %) was observed with the addition of aerosolized colistin to iv treatment, whereas the addition of aerosolized colistin did not affect overall mortality (OR, 0.74; 95 % CI: 0.54 to 1.01; p = 0.06; I2 = 25 %) or nephrotoxicity (OR, 1.18; 95 % CI: 0.76 to 1.83; p = 0.45; I2 = 0 %).  The authors concluded that based on the present results and awaiting further evidence from randomized trials, aerosolized colistin is associated with improved outcome in the treatment of ventilator-associated pneumonia although the level of evidence was low.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Other CPT codes related to the CPB:
94664	Demonstration and/or evaluation of patient utilization of an aerosol generator, nebulizer, metered dose inhaler or IPPB device
99503	Home visit for respiratory therapy care (e.g., bronchodilator, oxygen therapy, respiratory assessment, apnea evaluation)
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
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-10 codes not covered for indications listed in the CPB:
J01.00 - J01.91	Acute sinusitis
J32.0 - J32.9	Chronic sinusitis

The above policy is based on the following references: