Corinne Levy

Impact of 13-valent pneumococcal conjugate vaccine on pneumococcal nasopharyngeal carriage in children with acute otitis media.

Background: 13-valent pneumococcal conjugate vaccine (PCV13) licensure was based on the immune response (enzyme-linked immunosorbent assay and opsonophagocytic assay) compared with PCV7. National surveillance program of pneumococcal nasopharyngeal (PNP) carriage in children with acute otitis media (AOM) was set up in 2001 when PCV7 was introduced in France and continues to the present. This program was used in 2010–2011 to assess the effect of the implementation of PCV13 on PNP carriage in young children with AOM. Methods: Between October 2010 and March 2011, 58 pediatricians obtained 943 nasopharyngeal swabs from children (6 to 24 months of age) with AOM. The swabs were sent for analysis to the French National Reference Centre for Pneumococci. Demographics, medical history, and physical examination findings were recorded. Results: Among 943 children enrolled (mean age, 13.4 months), 651 had received at least 1 dose of PCV13 and 285 received PCV7 only. Among PCV13-vaccinated children, overall PNP carriage and carriage of serotypes not in PCV7 were significantly lower as compared with children exclusively vaccinated with PCV7 (53.9% vs. 64.6%, P = 0.002 and 9.5% vs. 20.7%, P < 0.0001, respectively). For serotypes 19A, 7F, and 6C, the carriage rates were also significantly lower in PCV13-vaccinated patients than in patients only vaccinated by PCV7: 7.5% versus 15.4%, P < 0.001, 0.5% versus 2.8%, P = 0.002, and 3.7% versus 8.4%, P = 0.003, respectively. Conclusion: In young children (<2 years) with AOM, this study suggests that PCV13 has an impact on overall PNP carriage, as well as on serotypes 19A, 7F, and 6C.

Impact of Pneumococcal Conjugate Vaccine and of Reduction of Antibiotic Use on Nasopharyngeal Carriage of Nonsusceptible Pneumococci in Children With Acute Otitis Media

Background: Penicillin resistance among pneumococci has increased in the past 15 years. The implementation of widespread vaccination with the heptavalent pneumococcal conjugate vaccine (PCV7) and the reduction of inappropriate antibiotic use could help reduce antibiotic resistance. Methods: Between September 2001 and June 2004, 89 pediatricians distributed throughout France took part in this prospective study. We obtained 1906 nasopharyngeal swabs for culture from children aged 6 to 24 months with acute otitis media (AOM). At the same time as PCV7 was introduced into the routine immunization schedule, a plan to promote judicious antibiotic use was established. We recorded the frequency of antibiotic use, as well as the dates of immunization with PCV7. Results: The proportion of PCV7-vaccinated children (≥1 dose) increased from 8.2% (year 1) to 61.4% (year 3). The proportion of children who received antibiotics within 3 months before enrollment decreased from 51.8% in year 1 to 40.9% in year 3 (P < 0.001). Overall pneumococcal carriage and carriage of PCV7 serotypes decreased during the 3-year period by 16% (P < 0.001) and 35% (P < 0.001), respectively. Rates of highly penicillin resistant strains (PRP) decreased yearly: 15.4%, 10.6%, 6.7% (P < 0.001), respectively. Risks for PRP carriage were 4.2% for immunized children who had not received antibiotics, 8.6% for those vaccinated who also had received antibiotics, 10.3% for unimmunized children who had not received antibiotics, and 16.2% for unimmunized children who had received antibiotics (P < 0.001). Conclusion: Implementation of PCV7, combined with a reduction in antibiotic use, in a country with a high prevalence of antibiotic-resistant pneumococci appears to have a strong impact on the carriage of penicillin nonsusceptible pneumococci in children with AOM.

Multinational study of pneumococcal serotypes causing acute otitis media in children

Background. Streptococcus pneumoniae is a major cause of acute otitis media (AOM) in young children. More than 90 immunologically distinct pneumococcal serotypes have been identified, but limited information is available regarding their relative importance in AOM. Methods. We analyzed nine existing datasets comprising pneumococcal isolates from middle ear fluid samples collected from 1994 through 2000 from 3232 children with AOM from Finland, France, Greece, Israel, several East European countries, the US and Argentina. We examined the distribution of pneumococcal serotypes in relation to several demographic and epidemiologic variables, including gender, age, antibiotic resistance and source of culture material. Results. The major serotypes identified included 19F and 23F, each comprising 13 to 25% of pneumococcal middle ear fluid isolates in most datasets; 14 and 6B, comprising 6 to 18%; whereas 6A, 19A and 9V each comprised 5 to 10%. Despite differences in location, study design and antibiotic susceptibility, each major serotype was prominent in most age groups of each dataset. Serotypes represented in the 7-valent pneumococcal conjugate vaccine (PCV-7, 4, 6B, 9V, 14, 18C, 19F, 23F) accounted for 60 to 70% of all pneumococcal isolates in the 6- to 59-month age range, but only 40 to 50% of isolates in children <6 or ≥60 months old. Serotype 3 and, in certain datasets, serotypes 1 and 5, were more important in the <6- and ≥60-month age groups. In each age group vaccine-related serotypes (mainly 6A and 19A) comprised an additional 10 to 15% of all pneumococcal isolates. Four serotypes (23F, 19F, 14 and 6B) accounted for 83% of all penicillin-resistant observations. Conclusions. This analysis of several geographically diverse datasets indicates that a limited number of serotypes, largely represented in PCV-7, accounted for the majority of episodes of pneumococcal AOM in children between 6 and 59 months of age. Certain serotypes appeared to be relatively more significant in children <6 months or >59 months of age.

Neonatal Bacterial Meningitis: 444 Cases in 7 Years.

Background: Neonatal bacterial meningitis remains a severe infectious disease with mortality rates varying between 10% and 15%. The clinical and bacteriologic features of neonatal meningitis collected from January 2001 to December 2007 in a French national survey are presented here. Methods: Cases of neonatal meningitis were prospectively collected by a network of 252 pediatric wards covering 61% of French pediatric wards, associated with 168 microbiology laboratories. Neonatal meningitis was classified as early-onset (d0–d4) and late-onset (d5–d28). Statistical analyses were performed according to gestational age and weight at birth. Results: A total of 444 cases of neonatal bacterial meningitis were reported by 114 pediatric wards. Five cases were excluded from analysis. Group B streptococci (GBS) and Escherichia coli accounted respectively for 59% and 28% of the cases, followed by Gram-negative bacilli other than E. coli (4%), other streptococci (4%), Neisseria meningitidis (3%), and Listeria monocytogenes (1.5%). GBS was the most common pathogen both in early-onset (77% vs. 18% for E. coli) and in late-onset meningitis (50% vs. 33% for E. coli). Among preterm infants, E. coli was more commonly isolated (45% vs. 32% for GBS), especially in very preterm infants (54%). GBS was more often involved in seizures than E. coli (41% vs. 25%). The overall mortality rate was 13% but reached 25% in preterm or small for gestational age infants, regardless of the etiology. Conclusions: GBS was the dominant cause of neonatal bacterial meningitis, with 77% of early-onset and 50% of late-onset cases. E. coli was the most common bacteria in preterm infants.

Bacterial Meningitis in Children: A French Prospective Study

From January 2001 through December 2003, a total of 1084 children with bacterial meningitis were enrolled in a prospective French nationwide survey. The most frequent pathogens found in children older than 28 days were Neisseria meningitis (55.3%) and Streptococcus pneumoniae (33.4%). S. pneumoniae was the most frequent pathogen found among infants aged 2-12 months (49.5%), whereas N. meningitidis was the most frequent pathogen among children >12 months old (69.7%). Approximately one-half of S. pneumoniae isolates had diminished susceptibility to penicillin. The case-fatality rates were 7.6% for children with N. meningitidis meningitis and 10.8% for children with S. pneumoniae infection.

Impact of Antimicrobial Therapy on Nasopharyngeal Carriage of Streptococcus pneumoniae, Haemophilus influenzae, and Branhamella catarrhalis in Children with Respiratory Tract Infections

We conducted a multicenter prospective study to document changes in nasopharyngeal carriage of Streptococcus pneumoniae, Haemophilus influenzae, and Branhamella catarrhalis during antibiotic therapy. A cohort of 629 children with respiratory tract infections underwent nasopharyngeal sampling before and after antibiotic treatment. Susceptibility testing, serotyping, arbitrarily primed polymerase chain reaction, and pulsed-field gel electrophoresis were used to compare pretreatment and posttreatment strains of S. pneumoniae. A significant decrease in carriage of all 3 species (especially S. pneumoniae and B. catarrhalis) was recorded. The increase in the proportion of penicillin-resistant pneumococci (PRP; 66% vs. 44%) was due to the decreased carriage of penicillin-susceptible pneumococci (71 of 629 vs. 176 of 629). The risk of PRP carriage in a given child did not increase. None of the children was found to harbor genetically related strains with increased minimum inhibitory concentrations. Given the multiple resistance of PRP, beta-lactam antibiotic therapy also increased the incidence of macrolide-resistant strains, whereas macrolides selected both macrolide- and penicillin-resistant strains.

Dynamic of pneumococcal nasopharyngeal carriage in children with acute otitis media following PCV7 introduction in France.

To determine whether the use of seven valent pneumococcal conjugate vaccine (PCV7) caused a shift in the Streptococcus pneumoniae serotypes distribution and whether it modified the resistance to antibiotics, 3291 nasopharyngeal swabs were obtained between 2001 and 2006, from children aged 6-24 months with acute otitis media. Following the implementation of PCV7, we observed a slight reduction in the overall pneumococcal carriage, a marked decrease of vaccine serotypes, an increase in non-vaccine serotypes carriage and a reduction in the carriage of penicillin non-susceptible strains. Most of the serotype 19A replacement was related to the clonal expansion of ST276 which was found to be the predominant ST among penicillin non-susceptible isolates.

Early Impact of 13-Valent Pneumococcal Conjugate Vaccine on Community-Acquired Pneumonia in Children

BACKGROUND Pneumococcal serotypes 1, 3, 5, 7F, and 19A were the most implicated in community-acquired pneumonia (CAP) after implementation of 7-valent pneumococcal conjugate vaccine (PCV7). In France, the switch from PCV7 to 13-valent pneumococcal conjugate vaccine (PCV13) occurred in June 2010. An active surveillance network was set up to analyze the impact of PCV13 on CAP. METHODS An observational prospective study performed in 8 pediatric emergency departments from June 2009 to May 2012 included all children between 1 month and 15 years of age with chest radiography-confirmed pneumonia. Three 1-year periods were defined: pre-PCV13, transitional, and post-PCV13. RESULTS During the 3-year study period, among the 953 274 pediatric emergency visits, 5645 children with CAP were included. CAP with pleural effusion and documented pneumococcal CAP were diagnosed in 365 and 136 patients, respectively. Despite an increase (4.5%) in number of pediatric emergency visits, cases of CAP decreased by 16% (2060 to 1725) between pre- and post-PCV13 periods. The decrease reached 32% in infants in the same periods (757 to 516; P < .001). Between pre- and post-PCV13 periods, the proportion of CAP patients with a C-reactive protein level >120 mg/dL decreased from 41.3% to 29.7% (P < .001), the number of pleural effusion cases decreased by 53% (167 to 79; P < .001) and the number of pneumococcal CAP cases decreased by 63% (64 to 24; P = .002). The number of additional PCV13 serotypes identified decreased by 74% (27 to 7). CONCLUSIONS Our data suggest a strong impact of PCV13 on CAP, pleural effusion, and documented pneumococcal pneumonia, particularly cases due to PCV13 serotypes.

A multicenter, randomized, double-blind trial of 5 versus 10 days of antibiotic therapy for acute otitis media in young children.

BACKGROUND All but 2 of the 15 published trials have failed to show a difference in efficacy between short (3 to 5 days) and standard (7 to 10 days) antibiotic regimens for acute otitis media (AOM). These studies involved relatively few patients under 2 years of age, who are at a higher risk for treatment failure. METHODS In a prospective, comparative, double-blind, randomized, multicenter trial, we compared amoxicillin/clavulanate in 3 divided doses for 10 days with an identical 5-day regimen, followed by a 5-day placebo period. RESULTS Between February 1995 and May 1996, 385 children (mean age, 13.3 months) were enrolled, 194 in the 5-day treatment group and 191 in the 10-day treatment group. In the per protocol analysis, clinical success was obtained on days 12 to 14 after the beginning of treatment (main analysis) in 125 (76.7%) of the 163 children receiving the 5-day regimen and 148 (88.1%) of the 168 receiving the 10-day regimen (P = .006). Clinical success persisted on days 28 to 42 among 57 (40.4%) of the 141 assessable patients in the 5-day group and 64 (46%) of the 139 assessable patients in the 10-day group. (P = .34). Multivariate analysis showed that the 10-day course was statistically superior only among children cared for outside their homes (86.8% vs 70.8%; P = .008). CONCLUSIONS When assessed on days 12 to 14 after the outset of treatment, a 5-day regimen is not equivalent to a 10-day regimen among young children with AOM.

Comparison of two dosages of azithromycin for three days versus penicillin V for ten days in acute group A streptococcal tonsillopharyngitis.

Background. Three-day, 10 mg/kg/day azithromycin (AZM) studies in pediatric acute group A streptococcal tonsillopharyngitis have shown contradictory bacteriologic results. This study investigates the efficacy and tolerability of two dosages of 3-day azithromycin (20 mg/kg/day and 10 mg/kg/day) compared with 10-day penicillin V. Methods. This was a prospective, comparative, randomized, multicenter trial. Children were scheduled to return for visits at 14 days (main end point) and 1 month after the onset of treatment for clinical and bacteriologic assessment. Molecular tools were used to compare pre- and posttreatment group A beta-hemolytic Streptococcus (GABHS) isolates. Results. Between November, 1997, and July, 1998, 501 patients (169 AZM 10 mg, 165 AZM 20 mg, 167 penicillin V) between 2 and 12 years old were enrolled; 500 were assessable for safety, 469 for intent to treat analysis and 420 for efficacy in the per protocol analysis. Before treatment 25 (7.9%) of 315 GABHS stains isolated from patients receiving AZM were resistant to this compound. On Day 14 pretreatment GABHS were eradicated from 78 (57.8%) of the 135 children receiving the AZM 10 mg regimen, 131 (94.2%) of the 139 receiving AZM 20 mg and 123 (84.2%) of the 146 taking penicillin. One month after the outset of treatment, bacteriologic relapses were observed in 40.5% (n = 30) of the children receiving AZM 10 mg, 14.8% (n = 18) of children taking AZM 20 mg and 13.2% (n = 15) of those treated with penicillin V. AZM 20 mg/kg/day was statistically superior to AZM 10 mg/kg/day microbiologically on Day 14 (P = 0.0001) and Day 30 (P = 0.0001) and clinically on Day 14 (P = 0.0035). AZM 20 mg/kg/day was statistically equivalent both microbiologically and clinically to standard therapy with penicillin V at all endpoints. The incidence of treatment-related adverse events was similar in the two azithromycin groups [AZM 10 mg, 31 of 169 (18.3%); AZM 20 mg, 37 of 164 (23%)] but significantly higher than those observed in the penicillin V group [5 of 166 (3%);P < 0.0001]. Most treatment-related adverse events were gastrointestinal and of mild-to-moderate severity. Fourteen patients withdrew from the trial because of adverse events (1 in the penicillin V group, 7 in the AZM 10 mg group and 6 in the AZM 20 mg group). Conclusion. This is the first study to demonstrate a daily dose-dependent difference in microbiologic efficacy of a regimen; 3-day AZM 20 mg/kg/day is a more effective regimen than 3-day AZM 10 mg/kg/day for pediatric GABHS tonsillopharyngitis.