Pneumococcal immunization and treatment implications for AOM

November 2004

Strategies for the use of antibiotics in the treatment of acute otitis media (AOM) have undergone significant change within the past several years, from recommendations in 1999 by the Drug-resistant Streptococcus pneumoniae Therapeutic Working Group for the use of higher doses of amoxicillin, to the use of no antibiotics (“observation” option) in select patients, as endorsed this year by the AAP. A major factor affecting these treatment recommendations has been the increasing prevalence of antibiotic resistance displayed by S. pneumoniae, the most common bacterial pathogen in AOM. Published evidence is now emerging describing the impact of the heptavalent pneumococcal conjugate vaccine (PCV7, Prevnar, Wyeth) on the microbiologic causes of AOM. This month’s column will discuss the potential impact of pneumococcal immunization on the microbiology of AOM and the use of antibiotics.

The impact of PCV7

Block and colleagues evaluated the impact of PCV7 on the microbiology of AOM by comparing AOM isolates obtained from children pre- and post-PCV7 use in Kentucky. Children 7 to 24 months of age with severe or refractory AOM had middle ear fluid cultures taken and assessed during the periods January 1992–January 1998 (pre-PCV7 use) and July 2000–April 2003 (post-PCV7). More than 90% of children in this group practice had been immunized with PCV7 (three to four doses). The sample included 298 children pre-PCV7 (336 pathogens) and 81 children post-PCV7 (83 pathogens). Pre-PCV7 children were less likely to be otitis-prone, attend day care and receive antibiotics in the prior 30 days (P <.05). The two cohorts were otherwise similar demographically.

The proportion of pneumococcal pathogens among the two cohorts decreased from 48% to 31% (P < .05), and the proportion of nonsusceptible S. pneumoniae decreased from 25% to 19% (P >.05). Haemophilus influenzae and Moraxella catarrhalis increased from 50% to 66% (P <.05). These pathogens producing ß-lactamase increased from 32% to 47% of the total pathogens (P <.05). ß-lactamase–producing H. influenzae were cultured more commonly among post-PCV7 children who had received antibiotics within the previous 30 days than among pre-PCV7 children (P <.05). As well, S. pneumoniae were cultured less frequently in post-PCV7 children generally considered at higher risk of infection with nonsusceptible pathogens – those who were otitis-prone, attended day care or recently received antibiotics (all P <.05). PCV7 serotypes decreased from 70% to 36%, whereas vaccine-related serotypes (6A, 19A) increased substantially (from 8% to 32%). Nonvaccine serotypes also increased, although less so (from 22% to 32%).

Casey recently published results of an evaluation of the impact of PCV7 and the use of higher doses of amoxicillin on the microbiology of AOM. Middle ear fluid cultures were taken from 551 children (72% younger than 2 years) with AOM from a suburban community-based private pediatrics practice in Rochester, N.Y. The children had not responded after one to two empiric antibiotic treatment courses (persistent AOM) or had failed after 48 hours on treatment (treatment failure). Comparisons in pathogenic microbiology were made among patients from 1995-1997 (amoxicillin 40-50 mg/kg/day as initial therapy), 1998-2000 (amoxicillin 80-100 mg/kg/day as initial therapy), and 2001-2003 (amoxicillin 80-100 mg/kg/day and use of PCV7). Second-line antibiotics used included a variety of antibiotics commonly prescribed in routine practice, although amoxicillin-clavulanate or a cephalosporin was most commonly used. Universal use of PCV7 by the author’s clinical practice began in late 2000, although not all children received the full dosage schedule.

Overall, a 24% decrease in persistent AOM and AOM treatment failures was noted between 1995-1997 and 2001-2003 (P <.05). A decline in the isolation of S. pneumoniae from middle ear cultures occurred among these treatment periods (from 48% to 31%, P <.05), and an increase in H. influenzae (from 38% to 57%, P <.05). A change in the predominant pathogen occurred from 1995-1997 to 2001-2003 with a shift from S. pneumoniae to H. influenzae (and an increase in ß-lactamase–producing H. influenzae, 46% to 55%, P <.05). The proportion of resistant S. pneumoniae decreased throughout the periods (34% to 14%), although the difference was not significant. (Click here to read related story.)

Benefits may be offset

In an accompanying editorial to the above studies, Stephen I. Pelton, MD, raises several good points about PCV7 and its potential effects upon AOM. Other data are available that similarly demonstrate a shift in AOM pathogens toward H. influenzae, such as one of the published studies used to support the FDA approval of PCV7 for AOM (the Finnish Otitis Media Study Group). Although the spontaneous resolution rate of AOM caused by H. influenzae is greater than for S. pneumoniae, many middle ear fluid cultures growing H. influenzae were obtained from children who had received antibiotics within the previous month or who had persistent symptoms while receiving an antibiotic with activity toward ß-lactamase–producing H. influenzae. This suggests a persistence of the pathogen in the nasopharynx, which has been demonstrated in other studies. This is important because most cases of AOM result from middle ear reflux of pathogens from the nasopharynx. Several studies have demonstrated reductions in PCV7 serotype nasopharyngeal colonization after immunization.

PCV7 targets the pneumococcal serotypes 4, 6B, 9V, 14, 18C and 23F, which represent the majority of serotypes responsible for invasive disease. PCV7 is indicated to prevent acute otitis media as well as invasive disease. Efficacy rates in the studies (Eskola, Black) used for FDA approval of AOM prevention were approximately 6% to 7% (overall reduction in AOM by all pathogens). Efficacy rates for AOM caused by S. pneumoniae vaccine serotypes were greater – 57% to 65%. However, this efficacy can vary (25%-84%), depending upon the specific vaccine serotype. This is encouraging because some data have shown that most penicillin-resistant S. pneumoniae cultured from the middle ear of children younger than 2 years of age are serotypes contained in PCV7. In contrast, in children older than 2 years of age, less than 50% of AOM episodes result from PCV7 serotypes. The benefit of reductions of AOM caused by PCV7 serotypes may be somewhat offset by increases in AOM caused by nonvaccine S. pneumoniae serotypes, as shown by a 33% increase in AOM from nonvaccine serotypes (Eskola).

Treatment implications

What implications do the above data have for the treatment of AOM? Because of only modest reductions in AOM overall from the use of PCV7, AOM will certainly continue to be a common reason for office visits. It is likely that resistant S. pneumoniae as a cause of AOM will be reduced, although this can vary geographically, depending upon the prevalence of resistant S. pneumoniae and serotype distribution in specific geographic locations. This reduction in AOM caused by vaccine serotypes does not approach 100%, however, and resistant S. pneumoniae should continue to be considered when choosing antimicrobial therapy. The increase in H. influenzae, M. catarrhalis and ß-lactamase–producing strains as causes of AOM suggests the potential for wider use of antibiotics with good stability toward ß-lactamase, namely amoxicillin-clavulanate, cefuroxime, cefdinir (Omnicef, Abbott), cefpodoxime and ceftriaxone.

Because no clinical data exist demonstrating superior efficacy of one cephalosporin over another, drug choice often relates to other considerations, such as taste, cost, or clinical or patient preference. Cefuroxime and cefpodoxime, while both displaying good activity towards AOM pathogens, have not fared well in antibiotic suspension taste tests. Thus, compliance and administration may be problematic. Cefdinir has ranked much higher in taste tests. These oral cephalosporins are relatively expensive (when compared with amoxicillin), although cefuroxime is available as a generic tablet formulation. Cefdinir is approved for once-daily dosing, whereas cefuroxime and cefpodoxime are approved for twice-daily dosing. Thus, it remains that the “top three” antibiotics available to pediatricians treating AOM will continue to be amoxicillin, amoxicillin-clavulanate and ceftriaxone.

For more information:

• Block SL, Hedrick J, Harrison CJ, et al. Community-wide vaccination with the heptavalent pneumococcal conjugate significantly alters the microbiology of acute otitis media. Pediatr Infect Dis J. 2004;23:829-833.
• Casey JR, Pichichero ME. Changes in frequency and pathogens causing acute otitis media in 1995-2003. Pediatr Infect Dis J. 2004;23:824-828.
• Pelton SI. Commentary: modifying acute otitis media, implications of immunization with pneumococcal conjugate vaccine. Pediatr Infect Dis J. 2004;23:839-841.
• Eskola J, Kilpi T, Palmu A, et al. The Finnish Otitis Media Study Group. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med. 2001;344:403-409.
• Black S, Shinefield H, Fireman B, et al. Efficacy, safety, and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J. 2000;19:187-195.
• Harrison CJ. Changes in treatment strategies for acute otitis media after full implementation of the pneumococcal seven valent conjugate vaccine. Pediatr Infect Dis J. 2003;22:S120-S130.

• Edward A. Bell, PharmD, BCPS, is an associate professor of pharmacy practice at Drake University College of Pharmacy, and a clinical specialist at Blank Children’s Hospital, Des Moines, Iowa.