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More data needed on xylitol, a medical food product for AOM prevention
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As acute otitis media is one of the most common pediatric infectious diseases and accounts for a significant amount of antibiotic use, methods to reduce or prevent recurrent AOM would likely have an important effect.
A new medical food product, Xylarex (xylitol oral solution, Arbor Pharmaceuticals), became commercially available earlier this year. Xylarex, available only by prescription, is labeled for use for the dietary management of recurrent acute otitis media (RAOM).
Xylarex is categorized by the FDA as medical food product, which differs from labeling as a medication or drug. A medical food is defined by the FDA as “a food that is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.” A medical food also differs from the categories of foods for special dietary use and foods that make health claims. A medical food is intended for the specific dietary management of a disease or condition. Medical foods do not have to undergo premarket approval by the FDA, as opposed to medications, which require premarket FDA evaluation and approval.
Strategies for reducing or preventing RAOM include reducing viral respiratory tract infection, reducing nasopharyngeal colonization with pathogens responsible for AOM and enhancing specific antibacterial immunity. Many experts believe that data from numerous clinical studies demonstrate the benefit of antibiotics as prophylaxis to reduce AOM episodes (by decreasing nasopharyngeal colonization with bacterial otopathogens). This benefit is greatest in young children (aged 6 to 24 months) and in otitis-prone children. Active immunization with influenza and pneumococcal vaccine products may additionally reduce RAOM in some children.
Xylitol
Xylarex is a berry-flavored oral solution containing 3.3 gm of xylitol per 5 mL. Xylitol is a polyol sugar (a sugar alcohol), and is naturally found in some fruits and berries. It is widely used as a sweetener in a variety of foods (eg, Trident gum). No data, however, are available to document the efficacy or benefit of using xylitol from these various food products to reduce RAOM, and this use should be discouraged.
The proposed mechanism of action of xylitol is inhibition of bacterial growth and adherence of otopathogens (S. pneumoniae, H. influenzae) to nasopharyngeal epithelial cells, as demonstrated in several published in vitro studies. Four clinical efficacy studies have been published describing the clinical effects of xylitol solution on AOM episodes.
Clinical trials
The earliest clinical trial, published in 1996, evaluated 306 children (mean age 5 years) in Finland and compared children who received either xylitol chewing gum (8.4 gm/day) or sucrose chewing gum for two months in a randomized, double-blind manner.
Inclusion and exclusion criteria were not specified, although normal healthy children are described as study participants. Outcome measures included AOM occurrence, use of antibiotics, and nasopharyngeal carriage of S. pneumoniae. Xylitol dosing included two pieces of gum chewed five times daily after meals. At least one AOM episode was seen in 20.8% of children receiving sucrose gum vs. 12.1% of children receiving xylitol gum (P<0.05). Fewer children using xylitol gum received antibiotics than children using sucrose gum (P<0.05). There was no difference in the rate of carriage of S. pneumoniae.
The same researchers then evaluated xylitol and placebo in 757 children from Finland. Children (mean age 2-5 years) were randomized to one of five treatment groups: xylitol syrup, xylitol gum, xylitol lozenge, placebo syrup, or placebo gum for three months of treatment. Only the groups receiving syrup or gum were double blinded. Xylitol dosing included administration five times daily after meals (total daily dose of 10 gm). The primary outcome measure was AOM occurrence associated with symptoms of a respiratory infection. Diagnosis of AOM required the finding of middle ear effusion in tympanometry, signs of inflammation in the tympanic membrane, and the presence of symptoms of acute respiratory infection. AOM episodes occurred in 29% of children receiving xylitol syrup compared with 41% of children receiving placebo syrup (30% decrease, P<0.05). AOM episodes also decreased by 40% in children receiving xylitol gum (P<0.05). The incidence rate of AOM per person-year-risk was 3.03 for children receiving xylitol and 2.01 for children receiving placebo. The number of days on antimicrobials was decreased in children receiving xylitol compared with placebo (31.7 per person-year-risk vs. 25 per person-year-risk, respectively), although it is not clear if all antibiotic courses were for AOM. Several methodologic concerns can be raised about this study. No adverse effect monitoring was described in this study, and it is known than xylitol may cause abdominal distress. More children receiving xylitol syrup were dropped from the study than children receiving placebo syrup. Intent-to-treat analysis apparently was not utilized.
Although the syrup and gum groups were double-blinded, xylitol syrup was described as sweeter than placebo syrup, which may have unmasked blinding. As the mean age of enrolled children was greater than 2 and the number of enrolled children younger than 2 was not described, the applicability of the results to younger children (ie, children at greater risk of AOM) is questionable. Most children in this study received additional sources of xylitol preceding the trial and it is unknown how this may have affected the results. This study is listed in the package labeling describing product efficacy. A separate study is also listed in the package labeling describing the tolerability of xylitol. Children in this study who received xylitol solution (5 gm three times daily) experienced the most common adverse effect of excessive gas or loose stools/diarrhea at no greater rate than children receiving placebo.
Two additional trials were conducted and published by the same researchers.
A study published in 2002 evaluated xylitol solution (10 gm/day divided over five doses per day) and xylitol gum in a randomized, double blind, placebo- controlled manner.
Xylitol was given at the start of an acute respiratory infection. The rate of occurrence of AOM did not differ among the treatment and placebo groups and thus was ineffective in preventing AOM when administered at the onset of respiratory tract symptoms.
A study published in 2007 evaluated xylitol syrup and gum (9.6 gm/day) in children (mean age 4 years) for three months in a randomized, double blind, placebo-controlled manner, similar to the above studies. This study differed, however, in that xylitol was given three times daily. There were no differences in the occurrence of AOM in the treatment and control groups. The researchers attribute this lack of efficacy to the extended time period between xylitol doses, potentially allowing more time for pathogenic bacteria to adhere to nasopharyngeal epithelial tissue. Methodologic concerns also exist with this study. More children dropped out of the treatment group than the control group (P<0.05), and the most common reason for dropping out was refusal. Additionally, most of the study participants had used xylitol products preceding the study.
Conclusions
The approximate retail cost of Xylarex for a 30-day supply is $100. Product package labeling states that Xylarex is safe and effective in the dietary management of RAOM-prone children when consumed as frequently as five times daily (10 gm/day) over a three-month period.
Four published clinical efficacy studies have evaluated Xylarex. Two of these studies concluded that Xylarex was not effective. Xylarex was found to be effective in the remaining two studies, and the results of one of these studies is summarized in the package labeling. Dosing in this study was 5 mL five times daily, and each 5 mL dose was administered slowly to prolong oral contact time. Although some data demonstrate that Xylarex can reduce AOM episodes, several concerns exist with its use. Effective dosing determined in clinical studies is five times daily, which may be difficult. Dosing three times daily was found not to be effective in a clinical study, yet this dosing is described in the package labeling. Administering a 5 mL dose over five minutes to young children as described in clinical studies may also be difficult. More data are needed for children aged younger than 2 — children at greater risk of RAOM. Additional efficacy, safety and dosing data are needed before this product can be routinely recommended.
For more information:
- Hautalahti O, et al. Failure of xylitol given three times a day for preventing acute otitis media. Pediatr Infect Dis J. 2007;26:423-427.
- Tepiainen T, et al. Xylitol administered only during respiratory infections failed to prevent acute otitis media. Pediatrics. 2002;109:e19.
- Uhari M, et al. A novel use of xylitol sugar in preventing acute otitis media. Pediatrics. 1998;102:879-884.
- Uhari M, et al. Xylitol chewing gum in prevention of acute otitis media: double blind randomized trial. British Medical Journal. 1996;313:1180-1183.