542150
research-article2014
AOPXXX10.1177/1060028014542150Annals of PharmacotherapyWargo and Campbell
Letter to the Editor
Is Xylitol Effective in the Prevention of Acute Otitis Media?
Acute otitis media (AOM) is a highly prevalent illness in childhood and remains the most common condition for which antibacterial agents are prescribed for children in the United States.1 Avoidance of unnecessary treatment is especially important with increased concern for antimicrobial resistance.1,2 Strategies for the prevention of AOM include the following: administration of pneumococcal conjugate vaccine and influenza vaccine, breastfeeding for at least 6 months, and lifestyle changes such as avoidance of tobacco smoke exposure.1 The use of xylitol for the treatment and prevention of AOM has also been discussed. Xylitol is a 5-carbon polyol that has been used widely as a sweetening substitute for sucrose because of its potential preventive effect on dental caries through its inhibition of the growth and metabolism of cariogenic bacteria.3,4 Additionally, xylitol has been shown to inhibit the growth of Streptococcus pneumoniae, and its use in the prevention of AOM was first described in 1996.5 Several randomized controlled clinical trials have analyzed various dosage forms of xylitol, including gum, lozenge, and syrup, for the prevention and treatment of AOM (Table 1). Two early studies evaluating the use of xylitol demonstrated moderate efficacy of some xylitol formulations in reducing occurrence of AOM in children when administered 5 times daily over 3-month periods.5,6 The impracticality of high-frequency, long-term administration of xylitol as a prophylactic measure for AOM prompted researchers to examine limiting the use of xylitol for AOM prophylaxis to periods of acute upper-respiratory tract infection, but no efficacy was established when xylitol was administered during upper-respiratory tract infection.7 Two additional trials, including a recent 2014 publication that evaluated less-frequent, 3 times daily administration of xylitol formulations, were unable to show efficacy for the prevention of AOM.8,9 In 2011, a Cochrane Review assessed the efficacy and safety of xylitol in preventing AOM in children up to 12 years of age.10 Reviewers evaluated 4 of the 5 trials summarized above—all but the most recent—and came to the conclusion that there is fair evidence that prophylactic administration of xylitol in any form reduces the occurrence of AOM by 25% compared with controls (relative risk [RR] = 0.75; CI = 0.65 to 0.88). The differences in
Annals of Pharmacotherapy 2014, Vol. 48(10) 1389–1391 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028014542150 aop.sagepub.com
AOM occurrence as a function of xylitol dosage forms were examined as part of the Cochrane assessment. Of the dosage forms analyzed, xylitol chewing gum was found to be superior to xylitol syrup for prevention among healthy children (RR = 0.59; CI = 0.39 to 0.89), and there was no difference between xylitol lozenges and syrups in preventing AOM among healthy children (RR = 0.73; CI = 0.47 to 1.13). The number of patients included in the meta-analysis who received lozenges compared with the other dosage forms is a limitation of the direct comparison, but the nondifference perhaps denotes that the dosage form has little influence on overall prophylactic benefits of xylitol for AOM. The use of xylitol for the prevention of AOM is limited for several reasons. Perhaps most notable is the required frequency of dosing regardless of formulation. Even 3 times daily dosing would be unpractical for most children, and conclusive efficacy at a frequency less than 5 times daily has not been established. In published trials, xylitol content per dosage unit (0.7 to 1.6 g) was similar to that in commercially available products, and to achieve total daily doses, it required 6 to 15 pieces of gum or lozenge. With 4 of the 5 trials published by the same research group in Finland, one may question potential bias and the lack of generalizability of the results. However, the reported data were not homogeneous, and there is no indication of conflict of interest. Xylitol use as a possible adjunct to AOM prevention is discussed in the most recent AOM guidelines, and there is a suggestion that perhaps chewing gum and lozenges appear to be more effective than syrup; however, no recommendations for use are made.1 Although the meta-analysis of the Cochrane Review demonstrated that xylitol can reduce AOM occurrence when compared with controls, it does not warrant routine use. This is based on practical purposes regarding dosing frequency and compliance required for clinical effectiveness.
Brief Explanation of Topic Significance Acute otitis media (AOM) is one of the most common reasons for pediatric physician visits and accounts for a large portion of antibiotic prescribing. Current guidelines provide recommendations to reduce the overall incidence of AOM,
Downloaded from aop.sagepub.com at UNIV ARIZONA LIBRARY on June 8, 2015
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Annals of Pharmacotherapy 48(10)
Table 1. Review of Xylitol Trials.
Uhari et al (1996)5
Formulation(s), Daily Dose of Administration Xylitol (g) Frequency
Duration of Therapy
n
Age (months)
336
12-60
Gum, 8.4
5 Times/d
2 Months
857
12-60
Gum, 8.4; syrup, 10; lozenge, 10
5 Times/d
3 Months
1277
10-84
Gum, 8.4; syrup, 10; lozenge, 10
5 Times/d
1-3 Weeks, during acute URTI
663
7-84
Gum, 9.6; syrup, 9.6
3 Times/d
3 Months
326
6-71
Syrup, 15
3 Times/d
6 Months
Uhari et al (1998)6
Tapianinen et al (2002)7 Hautalahti et al (2007)8 Vernacchio et al (2014)9
Clinical Outcomes AOM occurrence decreased significantly for xylitol users compared with sucrose: •• Difference = 8.7%; (CI = 0.4%17%; P = 0.04) AOM occurrence decreased for each group compared with the controls but was only statistically significant for the gum and syrup formulations: •• Gum difference = 40% (CI = 10.0%-71.1%; P = 0.025) •• Syrup difference = 30% (CI = 4.6%-55.4%; P = 0.028) •• Lozenge difference = 20% (CI = −12.9% to 51.4%; P = 0.30) AOM occurrence was not significantly different between xylitol users of any formulation compared with controls: •• Gum difference = −3.1% (CI= −7.6% to 2.5%; P = 0.32) •• Syrup difference = −0.1% (CI = −8.9% to 8.8%; P = 0.98) •• Lozenge difference = −4.5% (CI = −11% to 1.8%; P = 0.16) AOM occurrence was not significantly different between xylitol and controls: •• Difference = 0.26% (CI = −0.71 to 0.19; P = 0.25) AOM occurrence was not significantly different between xylitol and controls: •• HR = 0.88 (CI = 0.61-1.3; P = 0.5)
Abbreviations: AOM, acute otitis media; URTI, upper respiratory tract infection.
but its impact on the health care system remains burdensome. Xylitol has been considered an alternative preventive strategy to AOM for a little over a decade, despite limited evidence. A recent Cochrane Review claimed fair evidence that the prophylactic administration of xylitol among healthy children attending day care centers reduces the occurrence of AOM. However, this review was based on limited data. Since this review, new evidence has been released regarding the effect of xylitol in the prevention of AOM.
Osteopathic Medicine Center for Drug Information and Research. These responses are not published. Ryan Wargo, PharmD, LECOM–Bradenton, Florida, USA Marcus Campbell, PharmD, LECOM–Bradenton, Florida, USA
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Explanation of Any Similar Works by the Author(s)
Funding
Authors routinely provide responses to drug information inquiries as part of the services provided by the Lake Erie College of
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Downloaded from aop.sagepub.com at UNIV ARIZONA LIBRARY on June 8, 2015
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Wargo and Campbell References 1. Lieberthal AS, Carroll AE, Chonmaitree T, et al. The diagnosis and management of acute otitis media. Pediatrics. 2013;131;e964-e999. 2. American Academy of Pediatrics/American Academy of Family Physicians, Subcommittee on Management of Acute Otitis Media. Clinical practice guideline: diagnosis and management of acute otitis media. Pediatrics. 2004;113:1451-1465. 3. Antonio AG, Pierro V, Mala LC. Caries preventive effects of xylitol-based candies and lozenges: a systematic review. J Public Health Dent. 2011;71:117-124. 4. Burt BA. The use of sorbitol- and xylitol-sweetened chewing gum in caries control. J Am Dent Assoc. 2006;137:190-196. 5. Uhari M, Kontiokari T, Koskela M, Niemela M. Xylitol chewing gum in prevention of acute otitis media: double blind randomised trial. BMJ. 1996;313:1180-1183.
6. Uhari M, Kontiokari T, Niemela M. A novel use of xylitol sugar in preventing acute otitis media. Pediatrics. 1998;102:879-884. 7. Tapianinen T, Luotonen L, Kontiokari T, Renko M, Uhari M. Xylitol administered only during respiratory infections failed to prevent acute otitis media. Pediatrics. 2002;109:e19. 8. Hautalahti O, Renko M, Tapiainen, Kontiokari T, Pokka T, Urahi M. Failure of xylitol given three times a day for preventing acute otitis media. Pediatr Infect Dis J. 2007;26:423427. 9. Vernacchio L, Corwin MJ, Vezina RM, et al. Xylitol syrup for the prevention of acute otitis media. Pediatrics. 2014;133:289295. 10. Azarpazhooh A, Limeback H, Lawrence HP, Shah PS. Xylitol for preventing acute otitis media in children up to 12 years of age. Cochrane Database Syst Rev. 2011;(11):CD007095. doi:10.1002/14651858.CD007095.pub2.
Downloaded from aop.sagepub.com at UNIV ARIZONA LIBRARY on June 8, 2015
research-article2014
AOPXXX10.1177/1060028014542150Annals of PharmacotherapyWargo and Campbell
Letter to the Editor
Is Xylitol Effective in the Prevention of Acute Otitis Media?
Acute otitis media (AOM) is a highly prevalent illness in childhood and remains the most common condition for which antibacterial agents are prescribed for children in the United States.1 Avoidance of unnecessary treatment is especially important with increased concern for antimicrobial resistance.1,2 Strategies for the prevention of AOM include the following: administration of pneumococcal conjugate vaccine and influenza vaccine, breastfeeding for at least 6 months, and lifestyle changes such as avoidance of tobacco smoke exposure.1 The use of xylitol for the treatment and prevention of AOM has also been discussed. Xylitol is a 5-carbon polyol that has been used widely as a sweetening substitute for sucrose because of its potential preventive effect on dental caries through its inhibition of the growth and metabolism of cariogenic bacteria.3,4 Additionally, xylitol has been shown to inhibit the growth of Streptococcus pneumoniae, and its use in the prevention of AOM was first described in 1996.5 Several randomized controlled clinical trials have analyzed various dosage forms of xylitol, including gum, lozenge, and syrup, for the prevention and treatment of AOM (Table 1). Two early studies evaluating the use of xylitol demonstrated moderate efficacy of some xylitol formulations in reducing occurrence of AOM in children when administered 5 times daily over 3-month periods.5,6 The impracticality of high-frequency, long-term administration of xylitol as a prophylactic measure for AOM prompted researchers to examine limiting the use of xylitol for AOM prophylaxis to periods of acute upper-respiratory tract infection, but no efficacy was established when xylitol was administered during upper-respiratory tract infection.7 Two additional trials, including a recent 2014 publication that evaluated less-frequent, 3 times daily administration of xylitol formulations, were unable to show efficacy for the prevention of AOM.8,9 In 2011, a Cochrane Review assessed the efficacy and safety of xylitol in preventing AOM in children up to 12 years of age.10 Reviewers evaluated 4 of the 5 trials summarized above—all but the most recent—and came to the conclusion that there is fair evidence that prophylactic administration of xylitol in any form reduces the occurrence of AOM by 25% compared with controls (relative risk [RR] = 0.75; CI = 0.65 to 0.88). The differences in
Annals of Pharmacotherapy 2014, Vol. 48(10) 1389–1391 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028014542150 aop.sagepub.com
AOM occurrence as a function of xylitol dosage forms were examined as part of the Cochrane assessment. Of the dosage forms analyzed, xylitol chewing gum was found to be superior to xylitol syrup for prevention among healthy children (RR = 0.59; CI = 0.39 to 0.89), and there was no difference between xylitol lozenges and syrups in preventing AOM among healthy children (RR = 0.73; CI = 0.47 to 1.13). The number of patients included in the meta-analysis who received lozenges compared with the other dosage forms is a limitation of the direct comparison, but the nondifference perhaps denotes that the dosage form has little influence on overall prophylactic benefits of xylitol for AOM. The use of xylitol for the prevention of AOM is limited for several reasons. Perhaps most notable is the required frequency of dosing regardless of formulation. Even 3 times daily dosing would be unpractical for most children, and conclusive efficacy at a frequency less than 5 times daily has not been established. In published trials, xylitol content per dosage unit (0.7 to 1.6 g) was similar to that in commercially available products, and to achieve total daily doses, it required 6 to 15 pieces of gum or lozenge. With 4 of the 5 trials published by the same research group in Finland, one may question potential bias and the lack of generalizability of the results. However, the reported data were not homogeneous, and there is no indication of conflict of interest. Xylitol use as a possible adjunct to AOM prevention is discussed in the most recent AOM guidelines, and there is a suggestion that perhaps chewing gum and lozenges appear to be more effective than syrup; however, no recommendations for use are made.1 Although the meta-analysis of the Cochrane Review demonstrated that xylitol can reduce AOM occurrence when compared with controls, it does not warrant routine use. This is based on practical purposes regarding dosing frequency and compliance required for clinical effectiveness.
Brief Explanation of Topic Significance Acute otitis media (AOM) is one of the most common reasons for pediatric physician visits and accounts for a large portion of antibiotic prescribing. Current guidelines provide recommendations to reduce the overall incidence of AOM,
Downloaded from aop.sagepub.com at UNIV ARIZONA LIBRARY on June 8, 2015
1390
Annals of Pharmacotherapy 48(10)
Table 1. Review of Xylitol Trials.
Uhari et al (1996)5
Formulation(s), Daily Dose of Administration Xylitol (g) Frequency
Duration of Therapy
n
Age (months)
336
12-60
Gum, 8.4
5 Times/d
2 Months
857
12-60
Gum, 8.4; syrup, 10; lozenge, 10
5 Times/d
3 Months
1277
10-84
Gum, 8.4; syrup, 10; lozenge, 10
5 Times/d
1-3 Weeks, during acute URTI
663
7-84
Gum, 9.6; syrup, 9.6
3 Times/d
3 Months
326
6-71
Syrup, 15
3 Times/d
6 Months
Uhari et al (1998)6
Tapianinen et al (2002)7 Hautalahti et al (2007)8 Vernacchio et al (2014)9
Clinical Outcomes AOM occurrence decreased significantly for xylitol users compared with sucrose: •• Difference = 8.7%; (CI = 0.4%17%; P = 0.04) AOM occurrence decreased for each group compared with the controls but was only statistically significant for the gum and syrup formulations: •• Gum difference = 40% (CI = 10.0%-71.1%; P = 0.025) •• Syrup difference = 30% (CI = 4.6%-55.4%; P = 0.028) •• Lozenge difference = 20% (CI = −12.9% to 51.4%; P = 0.30) AOM occurrence was not significantly different between xylitol users of any formulation compared with controls: •• Gum difference = −3.1% (CI= −7.6% to 2.5%; P = 0.32) •• Syrup difference = −0.1% (CI = −8.9% to 8.8%; P = 0.98) •• Lozenge difference = −4.5% (CI = −11% to 1.8%; P = 0.16) AOM occurrence was not significantly different between xylitol and controls: •• Difference = 0.26% (CI = −0.71 to 0.19; P = 0.25) AOM occurrence was not significantly different between xylitol and controls: •• HR = 0.88 (CI = 0.61-1.3; P = 0.5)
Abbreviations: AOM, acute otitis media; URTI, upper respiratory tract infection.
but its impact on the health care system remains burdensome. Xylitol has been considered an alternative preventive strategy to AOM for a little over a decade, despite limited evidence. A recent Cochrane Review claimed fair evidence that the prophylactic administration of xylitol among healthy children attending day care centers reduces the occurrence of AOM. However, this review was based on limited data. Since this review, new evidence has been released regarding the effect of xylitol in the prevention of AOM.
Osteopathic Medicine Center for Drug Information and Research. These responses are not published. Ryan Wargo, PharmD, LECOM–Bradenton, Florida, USA Marcus Campbell, PharmD, LECOM–Bradenton, Florida, USA
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Explanation of Any Similar Works by the Author(s)
Funding
Authors routinely provide responses to drug information inquiries as part of the services provided by the Lake Erie College of
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Downloaded from aop.sagepub.com at UNIV ARIZONA LIBRARY on June 8, 2015
1391
Wargo and Campbell References 1. Lieberthal AS, Carroll AE, Chonmaitree T, et al. The diagnosis and management of acute otitis media. Pediatrics. 2013;131;e964-e999. 2. American Academy of Pediatrics/American Academy of Family Physicians, Subcommittee on Management of Acute Otitis Media. Clinical practice guideline: diagnosis and management of acute otitis media. Pediatrics. 2004;113:1451-1465. 3. Antonio AG, Pierro V, Mala LC. Caries preventive effects of xylitol-based candies and lozenges: a systematic review. J Public Health Dent. 2011;71:117-124. 4. Burt BA. The use of sorbitol- and xylitol-sweetened chewing gum in caries control. J Am Dent Assoc. 2006;137:190-196. 5. Uhari M, Kontiokari T, Koskela M, Niemela M. Xylitol chewing gum in prevention of acute otitis media: double blind randomised trial. BMJ. 1996;313:1180-1183.
6. Uhari M, Kontiokari T, Niemela M. A novel use of xylitol sugar in preventing acute otitis media. Pediatrics. 1998;102:879-884. 7. Tapianinen T, Luotonen L, Kontiokari T, Renko M, Uhari M. Xylitol administered only during respiratory infections failed to prevent acute otitis media. Pediatrics. 2002;109:e19. 8. Hautalahti O, Renko M, Tapiainen, Kontiokari T, Pokka T, Urahi M. Failure of xylitol given three times a day for preventing acute otitis media. Pediatr Infect Dis J. 2007;26:423427. 9. Vernacchio L, Corwin MJ, Vezina RM, et al. Xylitol syrup for the prevention of acute otitis media. Pediatrics. 2014;133:289295. 10. Azarpazhooh A, Limeback H, Lawrence HP, Shah PS. Xylitol for preventing acute otitis media in children up to 12 years of age. Cochrane Database Syst Rev. 2011;(11):CD007095. doi:10.1002/14651858.CD007095.pub2.
Downloaded from aop.sagepub.com at UNIV ARIZONA LIBRARY on June 8, 2015
