Infection with non-vaccine pneumococcal serotypes becoming more prevalent

Issue: February 2009

Prevnar (Wyeth Lederle Laboratories), a Streptococcus pneumoniae conjugate vaccine, was approved for use in children in 2000.

Prevnar is a seven-valent conjugate vaccine (PCV7) and targets S. pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F.

PCV7 has proven to be a successful vaccine, and data are available describing decreases in rates of invasive and non-invasive disease due to S. pneumoniae. However, data documenting increasing rates of disease due to non-vaccine S. pneumoniae serotypes are becoming available. Serotype 19A has been increasingly identified as an important nonvaccine serotype, especially in younger children. Treatment strategies for infection are ill-defined, and some data indicate that 19A may display resistance to many commonly used antibiotics.

Edward A. Bell

Approximately 90 different serotypes of S. pneumoniae have been identified. Of these, seven serotypes were responsible for 80% of pneumococcal disease in young children, and it is these serotypes that are included in PCV7. The inclusion of these serotypes in PCV7 and its widespread use since 2000 have led to dramatic declines in disease in children younger than 5.

Population-based and laboratory-based surveillance data reported last year from the CDC’s Active Bacterial Core surveillance of several states, have shown that invasive pneumococcal disease (IPD) in children younger than 5 years of age in 2005 was 77% lower than rates in 1998-1999, prior to the widespread availability and use of PCV7. IPD is defined as isolation of pneumococcus from normally sterile body sites. Incidence rates of IPD in children younger than 5 years declined from 98.7 cases/100,000 in 1998-1999 to 23.4 cases/100,000 in 2005. This decline actually surpassed the goal established by Healthy People 2010. The greatest percentage decline — 82% — occurred in children younger than 1. Although these data are no doubt welcome and encouraging, they are partially tempered with additional data demonstrating that disease due to nonvaccine serotypes are increasing, the most common of these is serotype 19A. The greatest increase in IPD caused by NVS occurred in children younger than 1. In 2005, serotype 19A was responsible for 40% of IPD among children younger than 5 years of age. Overall rates of IPD plateaued during 2002-2005, primarily because of increased rates of IPD due to nonvaccine serotypes. In 2005, 7% of IPD cases were due to PCV7 serotypes, compared with 80% of cases in 1998-1999. Additional data from the CDC have shown that all-cause pneumonia resulting in hospitalization in children younger than 2 years was 35% lower in 2005-2006 compared with 1997-1999. Although these incidence rates cannot be directly attributed to use of PCV7, they are nonetheless encouraging.

Similar data are available documenting changes in disease caused by S. pneumoniae in children since the introduction of PCV7. S. pneumoniae isolates (N=393) from 104 U.S. institutions were collected in 2005-2006 from children 14 years and younger. Pneumococcal specimens were isolated from invasive and noninvasive sites, including ear and sinus specimens. Of the 393 isolates collected and evaluated, 10.9% were serotypes contained in PCV7, and 89.1% were not vaccine serotypes. The most prevalent identified was serotype 19A, accounting for 30.5% of all isolates. Of the serotype 19A isolates, 70% were isolated from children 2 years of age and younger. This study is notable as antibiotic sensitivities were also determined. Of the serotype 19A isolates, 35% were resistant to amoxicillin-clavulanate, and resistance rates were more than 50% for cefdinir, cefuroxime axetil, azithromycin, and TMP/SMX.

All of the 19A serotypes were sensitive to levofloxacin and 99% were sensitive to telithromycin (Ketek, Sanofi Aventis). Thus, of all of the 19A serotypes (N=120), 76.7% displayed resistance to more than one antibiotic, and 51.6% displayed resistance to more than three antibiotics.

Similar data are available from children 14 years and younger who presented with community-acquired respiratory tract infections to one of 114 study sites during 2001-2004. The proportion of PCV7 serotypes decreased from 65.1% in 2000-2001 to 27% in 2003-2004. In 2003-2004 the most common serotypes identified were not vaccine serotypes. Rates of resistance displayed by nonvaccine serotypes to penicillin, amoxicillin-clavulanate, erythromycin, and multidrug resistance, all increased significantly from 2001 to 2004.

The data described above demonstrate that serotype 19A has emerged as the most common pneumococcal serotype overall and displays significant resistance to antibiotics commonly used in children. Unfortunately, very few data on the treatment of disease caused by nonvaccine serotypes are available. In an evaluation of acute otitis media in children 6-36 months of age from 2003-2006 due to S. pneumoniae, serotype 19A was identified in nine of 59 children (Pichichero, 2007). Of these nine children, four children had been treated unsuccessfully with more than two antibiotics, including high-dose amoxicillin and three-dose ceftriaxone, and required tympanostomy tube insertion.

Levofloxacin was used successfully in five children. In another study, levofloxacin was evaluated in a double-tympanocentesis, open-label manner in 204 children (6 months – 4 years) with AOM or recurrent or persistent AOM. Overall, bacterial eradication occurred in 88% of bacteriologically evaluable subjects (84% when S. pneumoniae was identified). A clinical success rate of 94% and 92% was achieved overall, and for bacteriologically evaluable subjects, respectively. Serotyping of S. pneumoniae was not performed in this study. However, rates of eradication of S. pneumoniae by sensitivity to penicillin were evaluated. Eradication occurred in 16 of 20 children with AOM due to penicillin-nonsusceptible strains.

Of these, eradication occurred in seven of 10 children who had with penicillin-resistant strains.

Conclusion

The introduction and use of PCV7 has had a substantial effect on reducing infectious disease in children. An unintended consequence of PCV7 use, however, has been an increasing incidence of pneumococcal disease caused by non-vaccine serotypes. This increase in serotype specific disease is minor compared to the large positive effect that PCV7 has had overall on disease.

The increasing incidence of pneumococcal disease caused by serotype 19A cannot be solely attributed to PCV7, as other factors, such as antibiotic use patterns, may be additionally responsible.

As non-vaccine pneumococcal serotypes and their effect upon disease continue to be defined, additional studies and data are needed. Identification of S. pneumoniae and specific serotypes remains important as well, as cultures of children with respiratory tract infections are not often taken, and serotyping of isolates may not be widely available.

As some data have indicated, currently available antibiotics for use in children may not be effective for disease caused by serotype 19A or other non-vaccine serotypes. Consideration should also be given to an antibiotic’s activity toward H. influenzae, as this pathogen’s role in AOM has also been altered by use of PCV7. The fluoroquinolone antibiotics, such as levofloxacin, may have a role to play, although additional data are needed to define this role.

The AAP issued recommendations on the use of fluoroquinolone antibiotics in 2006, stating that fluoroquinolones should be restricted to uses in which there is no safe and effective alternative treatment.

Additional pneumococcal vaccines may become available in the near future, as clinical studies of a 13-valent conjugate vaccine containing serotype 19A polysaccharide and a 10-valent conjugate vaccine, are in progress.

For more information:

Invasive pneumococcal disease in children five years after conjugate vaccine introduction – eight states, 1998-2005. MMWR. 2008;57:144-148
Pneumonia hospitalizations among young children before and after introduction of pneumococcal conjugate vaccine – United States, 1997-2006. MMWR. 2009;58:1-4
Critchley IA, et al. Prevalence of serotype 19A Streptococcus pneumoniae among isolates from US children in 2005-2006 and activity of faropenem. Antimicrobial Agents Chemo. 2008;52:2639-43
Farrell DJ, et al. Increased antimicrobial resistance among nonvaccine serotypes of Streptococcus pneumoniae in the pediatric population after the introduction of 7-valent pneumococcal vaccine in the United States. Pediatr Infect Dis J. 2007;26:123-8.
Pichichero ME, et al. Emergence of a multiresistant serotype 19A pneumoccal strain not included in the 7-valent conjugate vaccine as an otopathogen in children. JAMA. 2007;298:1772-8
Arguedas A, et al. An open-label, double tympanocentesis study of levofloxacin therapy in children with, or at high risk for, recurrent or persistent acute otitis media. Pediatr Infect Dis J. 2006;25:1102-9
Committee on Infectious Diseases. The use of systemic fluoroquinolones. Pediatrics. 2006;118;1287-92

Edward A. Bell, PharmD, is a Professor of Pharmacy Practice at Drake University College of Pharmacy, Blank Children’s Hospital in Des Moines, Iowa.