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Supplement: Acute Otitis Media: A Treatment Paradigm for the New Millennium

Nasopharyngeal colonization with pathogens causing otitis media: how does this information help us?

HARPER, MARVIN B. MD

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The Pediatric Infectious Disease Journal: December 1999 - Volume 18 - Issue 12 - p 1120-1124
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Information gathered from studies of nasopharyngeal (NP) colonization with microbial pathogens has been helpful in understanding risk factors for infection with these organisms, as well as for infection with organisms with reduced susceptibility to antibiotics. This article reviews data from these studies as they pertain to risk factors for otitis media and how this information is useful in guiding treatment. This article focuses on the pathogens that most commonly colonize the nasopharynx and cause otitis media: Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. Other pathogens, such as Streptococcus pyogenes, Staphylococcus aureus, Chlamydia trachomatis, Chlamydia pneumoniae, Mycoplasma pneumoniae and many viruses, are found in the nasopharynx and cause otitis media but occur much less often than the three primary pathogens.

NP colonization with bacterial pathogens is determined by a complex interplay of (1) exposure opportunity, i.e. the likelihood of sufficient exposure to someone carrying the organism; (2) factors effecting attachment of the organism to cells of the nasopharynx, including passive exposure to cigarette smoke, breast-feeding, age and immunity as acquired through prior exposure to that or similar organisms or prior immunization; and (3) the ability of the organism to remain a part of the resident flora, which again depends on immunity, the other resident flora and antibiotic use. In this article we discuss the epidemiology of NP colonization and its relationship to otitis media.

EPIDEMIOLOGY OF NP COLONIZATION

The relationship of age and NP carriage of S. pneumoniae is depicted in Figure 1.1 Approximately 50% of children carry S. pneumoniae at age 2 years, declining to 21% by age 7 years.2 Before 7 years of age ∼40% of children harbor M. catarrhalis, 30% H. influenzae and 2% S. pyogenes. Only ∼3% of adult day-care center employees are asymptomatic carriers of S. pneumoniae.2 In a study of a single cohort of 306 children followed from birth to 12 months, 68% of children had been colonized with a pathogen by 6 months of age. Colonization rates were highest for M. catarrhalis (55%), followed by S. pneumoniae (38%) and nontypable H. influenzae (19%). Colonization rates rose to 72, 54 and 33%, respectively, by 1 year of age.3 The most important risk factor for pneumococcal NP carriage is exposure to other young children (Table 1).1

Fig. 1
Fig. 1:
NP carriage of S. pneumoniae by age in the first 2 years of life. NP carriage was studied among healthy Israeli children seen at routine well-child-care visits. Modified with permission from Dagan et al.1
TABLE 1
TABLE 1:
Factors associated with increased NP carriage of pathogens

Interestingly the duration of colonization with any given strain of pneumococci does not appear to be very long. Ekdahl et al.4 utilized weekly NP cultures from a cohort of 678 individuals identified as carriers of penicillin-resistant pneumococci to determine the median duration of carriage of any specific strain as 19 days. The duration was longest for children <1 year of age (median, 30 days) and shortest in adults (median, 14 days). Other risk factors for prolonged NP carriage included frequent otitis media (conversely prolonged carriage could be the risk factor for frequent otitis media or specific immune factors may be responsible for both) and carriage by a family member. Overall S. pneumoniae spontaneously disappeared from the nasopharynx within 12 weeks in 94% of the individuals.4 Similarly nonencapsulated H. influenzae can cause high carriage rates with concurrent and successive colonization with multiple strains, generally with sequential elimination of dominant strains.5, 6 Those colonized with H. influenzae were much more likely to experience episodes of otitis media.7 No difference in the colonization rates of respiratory pathogens has been seen for breast-fed vs. formula-fed infants, however, despite the observation that the frequency of acute otitis media is lower in breastfed than in non-breast-fed children.8-10

Children who acquire NP colonization with bacterial pathogens in the first months of life are more likely to experience episodes of otitis media and to have more frequent episodes of NP colonization with S. pneumoniae than children who acquire first colonization at several months of age.3, 11 It has also become clear that infections caused by a specific strain of S. pneumoniae are most likely to do so within 1 month of establishing colonization and are seldom associated with prolonged carriage.12 In addition to a higher risk of acute otitis media among children with NP colonization of S. pneumoniae or H. influenzae,9 children harboring nonsusceptible pneumococci are more likely to experience episodes of unresolved acute otitis media.13, 14 Children with chronic otitis media with effusion are also highly likely to harbor a pathogen in the nasopharynx; in fact such patients tend to carry a higher number of pathogen species per patient as well as more colonies per patient.15, 16

Children with active upper respiratory tract infections are more likely to carry S. pneumoniae than those without.14, 17 In addition carriage of nontypable H. influenzae, S. pneumoniae and M. catarrhalis is more likely to be identified during episodes of otitis media compared with healthy periods. The quantity of nontypable H. influenzae, S. pneumoniae and M. catarrhalis in NP secretions is also increased during active infection compared with quantities during healthy periods, whereas the quantity of nonpathogenic resident NP flora (in particular, viridans streptococci) declines.18

The utility of colonization information to predict the causative organism for any given case of otitis media is poor. In studies in which cultures are simultaneously obtained from the middle ear fluid and the nasopharynx of children with acute otitis media, pathogens are more often recovered from the nasopharynx. Because of this, the predictive value of a positive NP culture is poor. Gehanno et al.19 found the positive predictive value of a positive NP culture to be ∼50% for H. influenzae species, 40% for S. pneumoniae and 20% for M. catarrhalis. However, it is rare to culture one of these pathogens from the middle ear without also recovering the pathogen from the NP culture; therefore the negative predictive value was good. A negative NP culture is accompanied by a negative middle ear fluid culture in >95% of children. This information comes only after treatment would have been routinely initiated. Furthermore the data are most desired when a pathogen is found and treatment is failing. Here, because the correlation of the isolated NP organism with the potential middle ear pathogen is not one-to-one, it is of dubious value for any individual patient.19, 20 When there is especially heavy growth of a particular pathogen in NP specimens, this may correlate well, however, with the organism causing otitis media.21

HOW ARE NP SWAB DATA USEFUL?

Trends in the serotypes and susceptibilities of S. pneumoniae causing otitis media are best obtained by recovering the isolates from the middle ear. These data, when available from large numbers of patients, then translate into information that can be used in determining appropriate empiric therapy for other, similar children as obtained by geographic region. It is not always possible to obtain this kind of data for specific populations. It is in these circumstances that evaluating the organisms causing NP colonization can serve as a useful surrogate for these data. S. pneumoniae NP isolates closely reflect the organisms causing invasive disease.22-24 Therefore NP swab data have been useful in identifying risk factors for harboring and incurring infections due to pneumococci with reduced antibiotic susceptibility (Table 2). Risk factors identified include current or recent antibiotic use, day-care attendance, living in an area with high antibiotic use and young age.25, 26

TABLE 2
TABLE 2:
Situations in which NP cultures are most helpful

Some children, such as those with sickle cell disease or human immunodeficiency virus infection, are of special concern. Because they are at increased risk of complications of infection, many such children receive antibiotic treatment prophylactically. Sickle cell patients on long term penicillin prophylaxis are less likely to carry S. pneumoniae in the nasopharynx (10 to 15% carriage) than other children, but when they do the proportion with reduced susceptibility to penicillin is increased. The results of NP culture surveys in special populations such as this need to be taken into consideration when evaluating the safety of antibiotic prophylaxis and making decisions about management in the setting of acute infections.27-31

NP culture studies have played and continue to play an important role in learning which factors influence the carriage and spread of pathogenic bacteria with reduced susceptibility to antibiotics. The rate of colonization with organisms with reduced susceptibility correlates with the overall community antibiotic usage, be it within a large geographic area or a smaller group, such as a day-care center, as well as with the individual history of antibiotic use.25 Such studies have also identified young age as being associated with a higher likelihood of carrying an organism with reduced susceptibility.

It is now recognized that S. pneumoniae resistance only rarely arises de novo, but instead clonal spread of a single resistant strain occurs from person to person. DNA analysis of NP isolates have revealed nonsusceptible strains in a cohort of children to generally be closely related.32-34 In addition, in any given day-care classroom (or even hospital setting) where resistant isolates are found, one strain will predominate, suggesting horizontal transmission.35, 36

The effect of antibiotic therapy on NP colonization with S. pneumoniae has been the subject of several recent and ongoing studies. Generally what can be seen is that children harboring penicillin-susceptible strains of S. pneumoniae will have a significant decrease in NP carriage in the first few weeks after treatment with a course of beta-lactam antibiotic. In contrast children carrying S. pneumoniae with reduced susceptibility to penicillin are less likely to have carriage eliminated. Therefore, although children treated with a beta-lactam antibiotic do not appear to acquire resistant strains, of those still carrying S. pneumoniae after treatment the proportion that has reduced susceptibility to penicillin has increased because the strains that are penicillin-susceptible have been disproportionately eliminated.37, 38, 39 The same may not be true for azithromycin. Dagan et al.40 observed that among 14 children receiving azithromycin, therapy eliminated all 6 azithromycin-susceptible S. pneumoniae strains, but not 2 initially resistant strains. Furthermore azithromycin-resistant strains were recovered from 2 additional patients initially negative for these strains. Leach et al.41 reported on the impact on pneumococcal colonization and resistance patterns resulting from a community-wide single dose azithromycin treatment project for all aboriginal children with trachoma and their household contacts. The proportion of children with azithromycin-resistant strains increased substantially in the 2 to 3 weeks after treatment (2% to 54%), and this proportion remained elevated above baseline for months after treatment when colonization rates had returned to baseline (at 2 months 78% of tested children were colonized with S. pneumoniae at which time 34% of isolated strains were azithromycin-resistant).

Carriage of S. pneumoniae with reduced susceptibility to penicillin has been correlated with the use of an antibiotic taken at a low daily dose, with a long duration of treatment or with use of an antibiotic with poor efficacy in vitro.42

AUGMENTING NATURAL IMMUNITY

Passive transfer of pooled human antibody by administration of an intramuscular injection of immunoglobulin (75 mg/kg of immunoglobulin administered every 3 weeks for 6 months) has not been helpful in reducing NP colonization with S. pneumoniae or the incidence of otitis media compared with controls.43 Similarly the polyvalent pneumococcal capsular polysaccharide vaccine did not significantly reduce the carriage rate of S. pneumoniae types present in the vaccine.44, 45 NP colonization with S. pneumoniae will change with the introduction of the new conjugate pneumococcal vaccines. It is known that NP colonization with vaccine-type strains is reduced after use of conjugate pneumococcal vaccines.46, 47 It is less clear whether this will translate into a reduction, increase or no change in the rates of colonization with nonvaccine serotypes and what overall impact this will have on the incidence of otitis media.

CONCLUSIONS

NP colonization is the portal through which pathogens gain access to the middle ear. There is little reason to obtain an NP swab for pathogens from healthy patients. NP swab testing is helpful in evaluating prevailing pathogens and their associated antibiotic susceptibilities in specific communities of patients. In addition NP culturing is useful in studying trends and the effect of interventions such as antimicrobial therapy and vaccination.

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Keywords:

Otitis media; Streptococcus pneumoniae; Haemophilus influenzae; Moraxella catarrhalis; microbial drug resistance; preschool; child; infant; child; human; nasopharynx/microbiology

© 1999 Lippincott Williams & Wilkins, Inc.