October 4, 2012 (San Francisco, California) — After the 7-valent pneumococcal conjugate vaccine (PCV-7) was introduced in the United States in 2000, there was a profound reduction in the number of children hospitalized for invasive disease caused by Streptococcus pneumoniae.
However, a new study has documented a significant rebound in the rates of disease, hospitalization, and antibiotic-resistant invasive disease. The results were presented here at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy.
Lead investigator Robertino Mera, MD, PhD, research associate at Management Systems International in Washington, DC, and a visiting professor at Vanderbilt University in Nashville, Tennessee, told Medscape Medical News that mathematical modeling had predicted such a pattern.
Dr. Mera and colleagues predict that a similar pattern will occur with the newer 13-valent pneumococcal conjugate vaccine (PCV-13), but not all experts agree.
"The vaccine had only 7 serotypes until 2010. Now we have 13," he said. Our mathematical model predicted that because of the replacement serotypes, "there was going to be replacement disease. And this is what you see," he explained.
The Rebound Effect
Dr. Mera and colleagues followed trends in hospitalization rates for invasive S pneumoniae to identify changes in the effectiveness of the vaccines. They used The Surveillance Network, from Eurofins Scientific, which collects information on strain-specific antimicrobial susceptibility data, and the Healthcare Cost and Utilization Project National Inpatient Survey for 1998 to 2009, which is a nationally representative sample of 20% of all hospitalizations in the United States.
The researchers found that from 1998 to 2002, the hospitalization rates for pneumococcal pneumonia decreased by 42% (95% confidence interval [CI], 28% to 54%) and for bacteremia decreased by 63% (95% CI, 49% to 73%). The effects were particularly pronounced after 2000, when PCV-7 was introduced. However, from 2003 to 2009, the rates climbed by 52% for pneumococcal pneumonia (95% CI, 10% to 105%) and by 39% for bacteremia (95% CI, 1% to 92%).
Despite the recent rebounds, the overall rate of pneumococcal pneumonias was still 12.5% less in 2009 than it was in 1998. For bacteremias, it was 47.0% less in 2009 than it was in 1998.
The largest increase in pneumococcal pneumonias was in children 2 to 5 years of age, at 80%. In 1999 there were about 4.7 cases per 1000 hospital discharges in this age group. In 2002, the rate dropped to 2.5 cases per 1000 discharges, but, in 2009, it rose to about 4.5 per 1000 discharges.
The vaccine had little effect in children younger than 2 years or older than 5 years, Dr. Mera explained. One-year-old children are just getting vaccinated and are therefore not immune, and few pneumonias occur in the children and adolescents 6 to 17 years of age.
From 2003 to 2009, there were significant increases in the number of children hospitalized with antibiotic-resistant isolates. Penicillin resistance increased 2.3-fold (95% CI, 1.7 to 3.3) and erythromycin resistance increased 1.96-fold (95% CI, 1.4 to 2.7). Additionally, the relative risk for hospitalization with cotrimoxazole-resistant isolates in 2009, compared with 2003, was 1.74 (95% CI, 1.2 to 2.4); for tetracycline-resistant isolates, it was 2.5 (95% CI, 1.7 to 3.7).
The researchers note that PCV-7 had a significant effect on the number of children hospitalized with pneumococcal-invasive disease, but that there was a significant rebound in the number of children 2 to 5 years of age hospitalized for pneumonia and bacteremia. The rebound was likely mediated by the rise in isolates resistant to commonly prescribed classes of antibiotics.
The researchers are now looking at trends in pneumococcal pneumonias since 2010, when PCV-13 was introduced. On the basis of mathematical modeling — validated by the drop and the rise in hospitalizations when PCV-7 was used — they expect to see similar effects with the 13-valent vaccine.
"That's why we need continuous surveillance of both resistance and nonvaccine serotypes.... It takes about 4 or 5 years for [a resurgence] to happen," he explained. "This will go on forever. It's the ecology of the transmission in the pediatric population," he added.
But Ron Dagan, MD, who was not involved with this study, does not agree. Dr. Dagan is professor of pediatrics and infectious diseases at the Ben-Gurion University of the Negev, director of the pediatric infectious disease unit at the Soroka University Medical Center in Beer-Sheva, Israel, and past president of the European Society for Paediatric Infectious Diseases and the World Society for Pediatric Infectious Diseases.
He explained to Medscape Medical News that the way pneumococcal pneumonia is defined is important. Some definitions are based on lobar disease and others require isolation of S pneumoniae, mostly from pleural effusions.
"The serotypes that are causing pleural effusion are typically not the serotypes in PCV-7," he said. Pleural effusion is more common in children 2 to 5 years than in those younger than 2 years. That difference might be related to the relative effectiveness of PCV-7 in those age groups, to the fact that pleural effusion is not caused by the serotypes in PCV-7, and to the increase in serotype 19a, which has become the predominant organism causing pleural pneumonia, he noted.
He is not surprised to see that the rate of pneumococcal pneumonia went down after introduction of PCV-13 because it protects against serotype 19a and other serotypes that cause pleural pneumonia.
Dr. Dagan and other experts predicted that PCV-7 was an incomplete vaccine and, therefore, expected to see the resurgence of pneumococcal pneumonia. He does not expect to see the same sort of resurgence with PCV-13. In his view, the resurgence after PCV-7 was multifactorial, related to antibiotic use, the fact that it was an incomplete vaccine, and the fact that there was some serotype replacement.
"PCV-13 is a more complete vaccine, so we don't have the same type of candidates to have this type of outbreaks," he said. "You'll still have pneumonia, you'll have mini-outbreaks with some of the serotypes...but they don't seem, at the moment, to be the same as the ones that are covered by PCV-13 [and] that were not covered by PCV-7," he explained.
Even though some of the remaining serotypes not included in PCV-13 are virulent, they might not cause an upsurge in disease. For them to replace other serotypes and cause disease, they would have to be prevalent, virulent, and adapted for carriage, and there is more chance for replacement if they are antibiotic resistant, Dr. Dagan noted.
"Then it's becoming a very successful bug to cause disease. At the moment we don't have such candidates, but they may evolve in the future," he allowed.
Dr. Mera reports having a research relationship with and being a shareholder in GlaxoSmithKline. Several coauthors are employees of GlaxoSmithKline. Dr. Dagan reports receiving speaker's and consultant fees and research support from Pfizer, GlaxoSmithKline, Novartis, and Merck.
52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC): Abstract G-862. Presented September 10, 2012.
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