Nonimmune strategies for prevention of otitis media

The strategies for prevention of otitis media (OM) include parent education, immunoprophylaxis, chemoprophylaxis, surgery and the use of innovative materials such as oligosaccharides and xylitol. In contrast to immunoprophylaxis, which protects against disease due to specific pathogens, the nonimmune strategies for prevention are generic and may have broad impact on the incidence of middle ear infections. All modes of prevention should be included in a strategy for the child who has severe and recurrent infections and who is “otitis-prone” because of known or unknown anatomic, physiologic or immunologic deficits. In this article I review the available data, benefits and limitations of each of the nonimmune techniques for prevention. PARENT EDUCATION Parents are partners in managing the child with recurrent and severe OM and should be empowered to use techinques to reduce risk for the child who is otitis-prone. Parents should know that: • OM is a disease of infancy. The child will have two or three bad winters, but most will have fewer problems with ear disease after 3 years of age. • Familial predisposition is a risk feature for severe and recurrent disease. There is a genetic predisposition to recurrent infections probably associated with anatomic, physiologic or immunologic features. The child born into a household with a history of ear infections in parent(s) or sibling(s) has a higher risk for recurrent and severe disease than the child born into a household without such a history. • Breast-feeding protects against AOM during the first year of life. Although not useful for the index case, the mother should consider breast-feeding for the next infant born into the family. • Large-group day care multiplies exposures to respiratory pathogens. The more children in the day-care group, the more exposures there are to microbial pathogens. Parents should understand the arithmetic of exposures in the day-care setting. • Smoking in the home causes irritation of the respiratory tract in household contacts. Children exposed to smoke have more episodes of OM than children in smoke-free environments. CHEMOPROPHYLAXIS Chemoprophylaxis is extensively used for prevention of disease due to specific pathogens, prevention of disease in infection-prone body sites and prevention of disease for the vulnerable host. The 24th edition of the Report of the Committee on Infectious Diseases of the American Academy of Pediatrics (1997) 1 lists 34 examples of appropriate uses of chemoprophylaxis including prevention of middle ear infections. The rationale for use of chemoprophylaxis for prevention of acute OM (AOM) is that a prolonged course of a modified dose of an antimicrobial agent will decrease the rate or intensity of colonization of the respiratory tract by bacterial pathogens. Criteria for appropriate use of chemoprophylaxis Because prolonged courses of any antimicrobial agent may have harmful effects including allergy, toxicity and development of multidrug-resistant bacteria, physicians must be assured that the benefits of decreased risk of infection outweigh the risk of prolonged usage of the drug. The criteria for appropriate usage of chemoprophylaxis are listed in Table 1. Recurrent episodes of AOM are of sufficient importance to warrant consideration of chemoprophylaxis, and the bacteriology of OM is well-documented and consistent. The penicillins and sulfonamides are available in a variety of convenient forms that are well-tolerated in infants and children. Drug toxicity is minimal with these two families of drugs, but allergic reactions are to be expected. Table 1: Criteria for appropriate use of chemoprophylaxisChemoprophylaxis and development of antibacterial resistance The most important concern, at present, is the risk of selective pressure of the drug for emergence of resistant organisms. Although there are considerable data about the incidence of multidrug-resistant strains after a course of antimicrobial drug for AOM, there is a paucity of data about the bacteriology and antimicrobial susceptibility of bacteria responsible for breakthrough episodes during chemoprophylaxis. The results of the few studies of middle ear aspirates from episodes of AOM during chemoprophylaxis suggest that the same species of bacteria, pneumococcus, Haemophilus influenzae and Moraxella catarrhalis are identified in breakthrough episodes, but there may be selection of resistant strains. In the observation period of a study of amoxicillin prophylaxis, Casselbrant et al. 2 found the same proportion of bacterial species responsible for breakthrough episodes in treated and control children; no unusual pathogens emerged to colonize the infants or cause AOM. Only the study by Brook and Gober 3 addressed the question of development of resistance during chemoprophylaxis; there was an increase in the proportion of penicillin-resistant bacteria in the oropharynx of 20 children during amoxicillin prophylaxis. Efficacy of chemoprophylaxis Many reports of controlled clinical trials of modified courses of antimicrobial agents compared with placebo, surgery or historical controls have been published. 4 The majority of studies used ampicillin/amoxicillin or a sulfonamide; a few evaluated penicillin V or a macrolide (e.g. erythromycin or azithromycin); some studies included children who received tympanostomy tubes. Most of the reports indicated benefit to the enrollees compared with the control groups: amoxicillin efficacy varied from 44 to 67%, but one study indicated no benefit 5; sulfonamide (including trimethoprim-sulfamethoxazole) efficacy was 40 to 88%, with 1 low result of 8%. 6 A metaanalysis summarizing results of studies of chemoprophylaxis concluded that the benefit to treated children was an average decrease in the number of episodes of AOM of 0.11 episode per patient per month or about 1 episode per year. 7 Children who were most likely to benefit from chemoprophylaxis were <2 years of age and in out-of-home child care. The efficacy of intermittent use of the prophylactic agent with first signs of upper respiratory tract infection was variable. 8–10 Because the signs of upper respiratory tract infection and AOM may be concurrent, intermittent use appears less likely to succeed than continuous use of chemoprophylaxis. Few of the studies evaluated middle ear effusion or asymptomatic middle ear effusion. Mandel et al. 11 identified efficacy of amoxicillin for prevention of recurrent episodes of OM with effusion and decreased percentage of time with middle ear effusion as well as decreased incidence of AOM. The rates per person per year of new episodes of AOM in the amoxicillin and placebo groups were 0.28 vs. 1.04, respectively; similarly, rates per person per year of new episodes of OM with effusion were 1.53 vs. 2.15, respectively. The results of the various studies of chemoprophylaxis should be evaluated separately rather than cumulatively because of the variations in criteria for enrollees, differences in number of patients evaluated, different durations of drug used and varying periods of observation. Nevertheless the pattern of decreased number of episodes in children who received prolonged courses of appropriate antimicrobial agents is consistent. Protocol for chemoprophylaxis In 1982 Bluestone and Klein proposed a plan for chemoprophylaxis in the first issue of the Pediatric Infectious Disease Journal (then called Pediatric Infectious Disease; January, 1982) that has continued to be of value over the years. 12 The following protocol was suggested: Who should have chemoprophylaxis? Chemoprophylaxis is appropriate for children who have had three distinct and well-documented episodes of AOM in 6 months or four episodes in 12 months. Because of the epidemiologic data indicating that children who have episodes of acute infection early in life or have siblings with severe and recurrent ear infections are otitis-prone, children who have one episode in the first 6 months and have a family history of ear infections or have two episodes in the first year of life may benefit from prophylaxis. Whichdrugs should be used? Amoxicillin, sulfisoxazole or trimethoprim-sulfamethoxazole have been used extensively and have the advantage of demonstrated efficacy, safety and low cost. Trimethoprim-sulfamethoxazole is effective and extensively used, but the manufacturer indicates in the package insert that the drug is not indicated for chronic OM. A recent survey for the period 1994 to 1998 (Table 2) by Thompson et al. (unpublished data, 1999) indicated that fewer children receiving prophylactic regimens had breakthrough episodes with use of amoxicillin and trimethoprim-sulfamethoxazole than with sulfisoxazole. Although local susceptibility data may influence choice of the prophylactic agent, amoxicillin would be my choice. Table 2: Episodes of acute otitis media during chemoprophylaxis (Boston, 1994 to 1998)What is the optimal dosage? One-half the therapeutic dose administered once a day (usually bedtime offers maximal compliance, but any consistent time during the day would be satisfactory): amoxicillin 20 mg/kg; sulfisoxazole 50 mg/kg. Recent recommendations by the Working Group for Resistant Streptococcus pneumoniae to double the therapeutic dosage of amoxicillin for AOM suggest that an increase in the prophylactic dosage may be warranted. 13 When should treatment be initiated and for what duration? The best time to begin chemoprophylaxis is during the fall, winter and spring periods when respiratory tract infections are most frequent. The regimen should be continued until the spring or summer when the incidence of respiratory tract infections decreases. What follow-up is appropriate? Children should be examined at least at 2-month intervals when free of acute signs, to determine whether middle ear effusion is present. Management of prolonged middle ear effusion should be considered separately from prevention of recurrences of acute infections. How should acute infections be treated? Acute infections are expected to occur during the course of prophylaxis. The infection should be treated with an alternative regimen. An effective oral cephalosporin or amoxicillin/clavulanate would be appropriate choices irrespective of the drug used for prophylaxis. SURGERY Some children will continue to have recurrent episodes of AOM despite chemoprophylaxis. Myringotomy and placement of tympanostomy tubes or adenoidectomy (with or without tonsillectomy) have been recommended for these otitis-prone children. Results of three clinical trials documented that myringotomy and tympanostomy tube insertion are effective for prevention of recurrent AOM. 2, 14, 15 Casselbrant et al. 2 reported that both amoxicilllin prophylaxis and myringotomy and tympanostomy tube insertion were more effective than placebo in prevention of recurrent AOM. Paradise et al. 16 demonstrated that children who had middle ear disease after placement of ventilating tubes benefited from subsequent adenoidectomy. However, adenoidectomy alone or adenoidectomy plus tonsillectomy without prior tympanostomy tubes showed only a modest benefit and only in the first year (of a 3-year period of observation) after the procedure. 17 The role of surgery in prevention of episodes of AOM follows medical management: tube placement should be considered the preferred surgical intervention; adenoidectomy should be reserved for those who develop recurrent OM with tubes in place or after extrusion of tubes. OLIGOSACCHARIDES Many viral and bacterial respiratory pathogens bind to carbohydrate receptors on the respiratory mucosa. Natural oligosaccharides act as decoys in the mucosa (also in saliva, tears, urine, sweat and breast milk) to bind to the carbohydrate-binding proteins of the microbial pathogens and prevent attachment. One of the major defenses for the neonate is the ability of oligosaccharides in breast milk to prevent bacterial attachment and protect against respiratory and enteric infections. Anderson et al. 18 demonstrated that a human milk oligosaccharide could inhibit binding of S. pneumoniae to desquamated cells of the human naso- and oropharynx. Zopf and Roth 19 described the potential of large scale manufacture of human oligosaccharides for use in studies of prevention of various infectious diseases including AOM. Oligosaccharides were demonstrated to interfere with the establishment and progression of experimental pneumococcal pneumonia. Intratracheal administration of the oligosaccharides together with bacteria decreased pneumococcal load in the lungs of rabbits and protected against bacteremia. Intranasally administered oligosaccharides prevented colonization of the nasopharynx of infant rats. 20 A trial of intranasally administered oligosaccharides for prevention of AOM in children in day care is under way now in Finland. XYLITOL Xylitol is a 5-carbon sugar alcohol that can be produced from birch trees, is found in fruits such as raspberries and plums and is used extensively as a sweetener in toothpaste, chewing gum and various foods. Because xylitol inhibits growth of Streptococcus mutans, it is used throughout Scandinavia and Great Britain for prevention of dental caries. Kontiokari et al. 21 demonstrated inhibition of growth of S. pneumoniae in vitro, stimulating the investigators to develop protocols for prevention of AOM. Two studies have been published that demonstrated efficacy of xylitol in prevention of AOM. In the first study xylitol or sucrose chewing gum was administered 5 times a day to 306 children in out-of-home group day care (mean age, 4.9 years). 22 During the 2-month period of observation, 1 or more episodes of AOM were experienced by 20% of children receiving sucrose gum compared with 12.1% of the children receiving xylitol gum. There was no difference in carriage of pneumococci in the treated and control children. In the second study 857 healthy children were recruited from out-of-home group day-care centers to receive a 5-times-a-day schedule of control or xylitol syrup, control or xylitol chewing gum or xylitol lozenge during a 3-month period of observation. 23 The incidence of rates of AOM per patient year were 3.03 in controls and 2.01 in the xylitol syrup group (P = 0.006); 1.69 in controls and 1.04 in the xylitol chewing gum group (P = 0.012); and 1.33 in the xylitol lozenge group. The higher rates in the syrup groups were due to the younger age of patients who received syrup rather than gum or lozenge. There results are promising but corroborative studies are needed to understand the pharmacokinetics of xylitol, to define the optimal administrative schedule (five times a day is likely to lead to poor compliance in most communities), to describe the mechanism of action of xylitol and to identify the efficacy of xylitol in children who are otitis-prone. CONCLUSIONS Prevention of OM is a priority for physicians, health care economists and parents. The promise of effective vaccines for prevention of AOM caused by pneumococci will likely be fulfilled with the availability of the conjugate pneumococcal polysaccharide vaccine. But many episodes of OM will still occur. Immunoprophylaxis is pathogen-specific. Nonimmune strategies for prevention are generic and are broadly applicable to AOM caused by various pathogens. For the child with severe and recurrent disease a multistep approach is needed: (1) use applicable vaccines; (2) consider chemoprophylaxis; (3) if chemoprophylaxis fails, consider myringotomy and placement of tympanostomy tubes; if children fail tympanostomy tubes consider adenoidectomy with replacement of tubes; and (4) empower parents to reduce risk features. Active research in products such as oligosaccharides that decrease attachment of bacteria to mucosal binding sites and products with favorable preliminary results, such as xylitol, may be of benefit in the overall strategy to reduce the burden of OM.