Introduction
Xylitol is a five-carbon sugar alcohol that is widely distributed in plants; it is found in significant concentrations in plums, strawberries and raspberries.Reference Wang and Van1 It is used as a bulking agent in foods, and as a low-caloric sweetener in medications, dental care products, chewing gums and candies.Reference Vernacchio, Vezina and Mitchell2 Xylitol may also be consumed by diabetics, as an insulin-independent dietary sweetener, having about one-third less calories than sugar.Reference Milgrom, Rothen and Milgrom3 In humans, xylitol is metabolised in the liver to glucose, glycogen and lactic acid. It affects blood glucose levels less than glucose does.Reference Natah, Hussien, Tuominen and Koivisto4 It has also been used as a component in parenteral nutrition.Reference Ladefoged, Berthelsen, Brockner-Nielsen, Jarnum and Larsen5
Xylitol is an unsuitable source of energy for many micro-organisms, and it inhibits the growth of Streptococcus pneumoniae in the presence of glucose.Reference Kontiokari, Uhari and Koskela6 It has anti-adhesive effects on both S pneumoniae and Haemophilus influenzae.Reference Kontiokari, Uhari and Koskela7 In addition, xylitol decreases the salt concentration of human airway surface liquid that contains many antimicrobial substances, including lysozyme, lactoferrin, human β defensins and cathelicidin LL-37.Reference Goldman, Anderson, Stolzenberg, Kari, Zasloff and Wilson8 Lowering the human airway surface liquid salt concentration can increase the efficacy of the innate immune system, and thereby decrease or prevent airway infections.Reference Durairaj, Launspach, Watt, Businga, Kline and Thorne9 Xylitol also reduces the adhesiveness of mutans streptococci to tooth biofilms and inhibits the growth of Streptococcus mutans, which is the most important bacterium in the development of dental caries.Reference Milgrom, Ly, Tut, Mancl, Roberts and Briand10 Xylitol exerts selective antibacterial-like actions against mutans streptococci by disrupting glucose cell-wall transport and intracellular glycolysis, thus inhibiting growth.Reference Miyasawa-Hori, Aizawa and Takahashi11
This review of contemporary literature aimed to evaluate the efficacy of xylitol usage in ENT practice. For this purpose, the English literature was searched using the following terms: xylitol, otitis media, nasal, sinusitis, dental caries and preventive therapy. The articles identified were included in this review.
Xylitol for acute otitis media
Acute otitis media is a common disease and is the main reason for antimicrobial treatment in children. Streptococcus pneumoniae is the most common bacterium causing middle-ear infections or sinusitis, and nasopharyngeal carriage of this bacterium has been shown to be a predisposing factor.Reference Faden, Waz, Bernstein, Brodsky, Stanievich and Ogra12 In their in vitro study, Kontiokari et al. showed that xylitol reduced the growth of S pneumoniae in the nasopharynx, and thus could reduce the carriage of bacteria.Reference Kontiokari, Uhari and Koskela6 This has clinical significance for preventing attacks of acute otitis media caused by pneumococci.
In 1996, a group from Finland (Uhari and colleagues) reported their first trial on xylitol chewing gum for the prevention of acute otitis media. In this randomised trial, a total dose of 8.4 g of xylitol was administered regularly in the form of chewing gum, five times a day for two months. This was shown to reduce the occurrence of acute otitis media by about 40 per cent when compared with a sucrose (control) gum group. However, unexpectedly, there was no decrease in the carriage rate over time in the xylitol group.Reference Uhari, Kontiokari, Koskela and Niemela13 Two years later, the researchers published the findings of a second trial. In that trial, xylitol was given in syrup form to those children who were not able to chew gum, and in gum or lozenges to those who were old enough to consume them, for three months. The authors reported a significant reduction in the occurrence of acute otitis media when xylitol chewing gum or xylitol syrup was administered five times daily. There was also a decrease in the occurrence of acute otitis media with xylitol lozenges, but the difference was not significant. The use of antimicrobials was significantly lower among those receiving xylitol syrup and xylitol chewing gum compared with their controls, but not in the lozenge group as compared with the control chewing gum group.Reference Uhari, Kontiokari and Niemela14 The results of the clinical trials reviewed in this paper are summarised in Table I.Reference Uhari, Kontiokari, Koskela and Niemela13–Reference Weissman, Fernandez and Hwang20
Table I Clinical trials on xylitol usage in ent practice
DBPCRT = double-blind, placebo-controlled, randomised trial; AOM = acute otitis media; PCRT = placebo-controlled, randomised trial; ARI = acute respiratory infection; TID = three times a day; COME = chronic otitis media with effusion; R = right; L = left; PTA = pure tone audiometry; FU = follow up; ASL = airway surface liquid; w/v = weight/volume; SNOT-20 = Sino-Nasal Outcome Test 20; VAS = visual analogue scale; CRS = chronic rhinosinusitis
The practicability of giving xylitol five times per day for preventing acute otitis media was questioned, but the group's search for more convenient ways of administering xylitol was not successful. In Uhari and colleagues' subsequent study (Tapiainen et al.), they reported that xylitol administered only during an acute respiratory infection was ineffective in preventing acute otitis media (Table I).Reference Tapiainen, Luotonen, Kontiokari, Renko and Uhari15 In addition, xylitol seemed to be ineffective when given immediately after the placement of tympanostomy tubes.Reference Uhari, Tapiainen and Kontiokari21 Later, Hautalahti et al. reported that xylitol given regularly three times a day during acute respiratory infection episodes for three months also failed to prevent the occurrence of acute otitis media (Table I).Reference Hautalahti, Renko, Tapiainen, Kontiokari, Pokka and Uhari16 The authors pointed out once more that continuous xylitol prophylaxis administered five times a day was able to effectively prevent acute otitis media attacks. In 2007, Vernacchio et al. demonstrated that oral xylitol solution, at dosages of 5 g three times a day and 7.5 g once daily, is reasonably well tolerated by and acceptable for children at the highest risk of recurrent acute otitis media.Reference Vernacchio, Vezina and Mitchell2 They suggested that clinical trials using these dosages of xylitol could be conducted, given the potential for xylitol as a safe, inexpensive option for acute otitis media prophylaxis. Hence, the search for the most suitable dosage of xylitol for acute otitis media prophylaxis continues.
In a systematic review published in 2010 on acute otitis media preventative treatment, Danhauer et al. stated that the prophylactic effects of xylitol have been shown in children with acute otitis media.Reference Danhauer, Johnson, Corbin and Bruccheri22 Xylitol is well tolerated in children, with minimal side effects. The best vehicle for administration in children is chewing gum. The act of chewing and swallowing assists with the disposal of earwax and clearing of the middle ear, whilst the presence of xylitol prevents the growth of bacteria in the eustachian tubes.23 As mentioned above, the Finnish group of researchers observed that 10 g of xylitol daily, given as 2 g orally five times a day, is well tolerated in children as young as nine months of age for acute otitis media prevention. Xylitol lozenges, however, seem to be poorly tolerated; abdominal discomfort and a dislike of the product are more common.Reference Uhari, Kontiokari, Koskela and Niemela13–Reference Tapiainen, Luotonen, Kontiokari, Renko and Uhari15
Sezen et al. investigated the effect of chewing gum containing xylitol on middle-ear pressure in children with chronic otitis media with effusion (Table I).Reference Sezen, Kaytancı, Eraslan, Coşkuner, Kubilay and Aydın17 The patients who received the xylitol chewing gum had more improvement in pressure levels for the right and left ears than those in the sorbitol group. However, there were no statistically significant differences between the groups in terms of the presence of glue in the middle ear or the pure tone audiometric results for right and left ears after the treatment.
Danhauer et al. mailed a 48-item questionnaire to a random sample of 506 paediatricians within the USA to assess their opinions on the prophylactic use of xylitol in children with acute otitis media.Reference Danhauer, Johnson, Corbin and Bruccheri22 The authors found that most of the paediatricians knew about the medical uses of xylitol and most were aware of its use in chewing gum to prevent acute otitis media. However, the majority had not used xylitol in their practice, and were not sure of the effectiveness or appropriate dosage.
In a case report, it was stated that nasally administered xylitol dramatically reduced acute otitis media episodes in children who previously suffered chronic ear complaints (Table I).Reference Jones18 In the same paper, two other patients with asthma were reported to benefit from nasal saline sprays containing xylitol.
Xylitol for rhinosinusitis
Bacteria are thought to play a central role in sinusitis. In establishing rhinosinusitis, bacteria first need to overcome the body's natural defences. In the treatment of rhinosinusitis, especially in refractory cases, attention on innate immunity has been limited.
Respiratory tract secretions contain a variety of antimicrobial factors, including lysozymes, lactoferrin, β-defensins, secretory phospholipase A2 and cathelicidins.Reference Ganz24 These antimicrobial factors reside in the thin layer of airway surface liquid. Experimentally lowering the airway surface liquid salt concentration increases the activity of endogenous antimicrobials. A promising osmolyte for lowering airway surface liquid ionic strength is sugar xylitol. Zabner et al. showed that xylitol can lower the airway surface liquid salt concentration in both cystic fibrosis and non-cystic fibrosis airway epithelia in vitro, and can thus enhance the innate immunity. In the nasal mucosa, xylitol spray was observed to reduce nasal staphylococcal carriage rates in normal volunteers (Table I).Reference Zabner, Seiler, Launspach, Karp, Kearney and Look19
In an experimental study, Brown et al. administered xylitol, saline and Pseudomonas aeruginosa to the rabbit maxillary sinus.Reference Brown, Graham, Cable, Ozer, Taft and Zabner25 They observed that the simultaneous administration of xylitol and P aeruginosa produced a statistically significant increase in bacterial killing after 20 minutes compared with normal saline. They reported that xylitol reduced experimentally induced sinusitis when administered simultaneously with bacteria, but its effect in established sinusitis was not clear.
Recently, Weissman et al. evaluated the effect of nasal irrigation with xylitol in subjects with chronic rhinosinusitis (Table I).Reference Weissman, Fernandez and Hwang20 Twenty subjects with chronic sinusitis were instructed to complete two sequential 10-day courses of daily xylitol and saline irrigations, in a randomised fashion. The authors observed a significant reduction in Sino-Nasal Outcome Test 20 scores associated with xylitol irrigation as compared with saline irrigation, indicating improved sinonasal symptoms for xylitol irrigation.
Miscellaneous studies on xylitol in ENT disorders
An in vitro study by Kontiokari et al. showed that xylitol markedly reduced the growth of α-haemolytic streptococci, including S pneumoniae.Reference Kontiokari, Uhari and Koskela6 In addition, it slightly reduced the growth of β-haemolytic streptococci, but not that of H influenzae or Moraxella catarrhalis. A later study by the same research group indicated the anti-adhesive effects of xylitol against both S pneumoniae and H influenzae in a mixture of oropharyngeal epithelial cells and bacteria.Reference Kontiokari, Uhari and Koskela7
In an experimental study, Renko et al. reported the beneficial effects of xylitol-supplemented nutrition on both the oxidative killing of bacteria in neutrophilic leucocytes and on the survival of rats with experimentally induced sepsis with S pneumoniae.Reference Renko, Valkonen, Tapiainen, Kontiokari, Mattila and Knuuttila26 Xylitol was also shown to be cytoprotective during oxidative stress.Reference Shangari and O'Brien27
In clinical trials, xylitol supplementation has been shown to decrease the occurrence of acute otitis media in day-care children; however, the nasopharyngeal carriage of the pneumococci was not reduced.Reference Uhari, Kontiokari, Koskela and Niemela13
The capsular cpsB gene is essential for encapsulation and for regulation of the production of capsular polysaccharide for streptococci.Reference Morona, Miller, Morona and Paton28 Kurola et al. showed that exposure to xylitol significantly lowered cpsB gene expression levels in S pneumoniae isolates.Reference Kurola, Tapiainen, Kaijalainen, Uhari and Saokkoriipi29 They reported that xylitol changed the ultrastructure of the pneumococcal capsule, which could explain the high clinical efficacy of xylitol in preventing otitis media without reducing nasopharyngeal carriage.
Xylitol safety and side effects
Xylitol is absorbed slowly by the gut wall and may cause loose stools when ingested in large amounts. Oral xylitol is well tolerated in adults and children. Whilst adults can tolerate daily doses of up to 200 g of xylitol without gastrointestinal symptoms, children can only tolerate daily xylitol doses of up to 45 g without gastrointestinal symptoms.Reference Makinen30, Reference Akerblom, Koivukangas, Puukka and Mononen31 In addition to loose stools, large amounts of xylitol may cause abdominal discomfort and osmotic diarrhoea.Reference Tapiainen, Luotonen, Kontiokari, Renko and Uhari15 These side effects do not appear particularly dependent on age or weight. It has been shown that adaptation to xylitol occurs rapidly, such that the laxative effect diminishes within several days of regular use.Reference Forster, Quadbeck and Gottstein32 Parenteral xylitol can cause minimal hyperuricaemia without any pathophysiological consequences.Reference Ladefoged, Berthelsen, Brockner-Nielsen, Jarnum and Larsen5 Though tolerated well in modest doses, large amounts of xylitol administered intravenously have been reported to cause reno-cerebral oxalosis with renal failure.Reference Pfeiffer, Weiss, Karger, Aghdassi, Lerch and Brinkman33
Conclusion
Acute otitis media is one of the most prevalent and costly illnesses in children throughout the world. The prophylactic use of antibiotics has the desired effect, but is liable to lead to the development of antimicrobial-resistant bacteria. Thus, new approaches are required to prevent acute otitis media. The efficacy of xylitol is comparable to that of the best-known prophylactic methods, such as continuous antimicrobial prophylaxis and surgical procedures. Xylitol delivered to the nasal or sinus mucosa may enhance innate bacterial defences by modifying the airway surface liquid salt concentration. Xylitol can be used to prevent the onset or delay the progress of rhinosinusitis. Furthermore, in populations with high rates of tooth decay, xylitol interventions are likely to be cost-effective. The worldwide spread of drug-resistant strains of pneumococci substantiates the need for new approaches to prevent ENT-related infectious diseases. Xylitol may be a promising agent for this purpose in ENT practice, but further experimental and clinical studies are required.
