Emmanuelle Varon

Bacterial Meningitis in Burkina Faso: Surveillance Using Field-Based Polymerase Chain Reaction Testing

BACKGROUND In addition to frequent epidemics of group A meningococcal disease, endemic bacterial meningitis due mostly to Neisseria meningitidis, pneumococcus, and Haemophilus influenzae type b is a serious problem in sub-Saharan Africa. The improved ability to identify the etiologic agent in cases of bacterial meningitis will facilitate more rapid administration of precise therapy. METHODS To describe the epidemiology of bacterial meningitis and evaluate the usefulness of field-based polymerase chain reaction (PCR) testing, we implemented population-based meningitis surveillance in Burkina Faso during 2002-2003 by use of PCR, culture, and antigen detection tests. RESULTS Among persons aged 1 month to 67 years, the incidences of meningococcal meningitis, pneumococcal meningitis, and Haemophilus influenzae type b meningitis were 19 cases (n=179), 17 cases (n=162), and 7.1 cases (n=68) per 100,000 persons per year, respectively. Of the cases of meningococcal meningitis, 72% were due to N. meningitidis serogroup W135. Pneumococcal meningitis caused 61% of deaths and occurred in a seasonal pattern that was similar to that of meningococcal meningitis. Of cases of pneumococcal meningitis and N. meningitidis serogroup W135 meningitis, 71% occurred among persons >2 years of age. Most patients, regardless of the etiology of their illness and the existence of an epidemic, received short-course therapy with oily chloramphenicol. Compared with culture as the gold standard, the sensitivity and specificity of PCR in the field were high; this result was confirmed in Burkina Faso and Paris. CONCLUSIONS Precise and rapid identification of etiologic agents is critical for improvement in the treatment and prevention of meningitis, and, thus, PCR should be considered for wider use in Africa. Vaccines against Streptococcus pneumoniae, N. meningitidis (including serogroup W135), and H. influenzae type b all will have a major impact on the bacterial meningitis burden. Antibiotic recommendations need to consider the importance of S. pneumoniae, even during the epidemic season.

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.

Microbiological Diagnosis of Empyema in Children: Comparative Evaluations by Culture, Polymerase Chain Reaction, and Pneumococcal Antigen Detection in Pleural Fluids

BACKGROUND Pleural empyema is an increasingly reported complication of pneumonia in children. Microbiological diagnostic tests for empyema by culture frequently have false-negative results due to previous administration of antibiotics. Molecular diagnosis by broad-range 16S ribosomal DNA (rDNA) polymerase chain reaction (PCR) and rapid pneumococcal antigen detection are reliable tools, but their diagnostic value has not been clearly established for pleural fluid samples. Pneumococcal antigen detection has only been validated for urine and cerebrospinal fluid samples. METHODS Over 4 years, pleural fluid specimens were collected from 78 children with pleural empyema. Standard culture, pneumococcal antigen detection by latex agglutination (Pastorex; Bio-Rad) and immunochromatographic testing (Binax NOW Streptococcus pneumoniae), and 16S rDNA PCR were performed on these specimens. Pneumococcal identification by 16S rDNA PCR and sequencing was confirmed by pneumolysin PCR. RESULTS Of the 78 cases of pleural empyema, 60 (77%) were microbiologically documented by culture or 16S rDNA PCR. Of the 40 pneumococcal empyema cases, 17 (43%) were only diagnosed by PCR and 23 with PCR and culture. The sensitivity and specificity of the latex antigen detection (with the use of culture and/or PCR as the test standard) were 90% and 95%, respectively. The immunochromatographic test detected pneumococcal antigens in 3 additional specimens for which latex agglutination results were negative, thereby increasing the sensitivity of antigen detection. CONCLUSIONS Pneumococcal antigen detection in pleural fluid specimens from children provides a rapid and sensitive method of diagnosis of pneumococcal empyema, which can be confirmed by specific pneumolysin PCR when culture results are negative. Broad-range 16S rDNA PCR has value in detecting bacterial agents responsible for culture-negative pleural empyema.

Reduction of Antibiotic Use in the Community Reduces the Rate of Colonization with Penicillin G—Nonsusceptible Streptococcus pneumoniae

BACKGROUND There is a lack of evidence documenting the impact of optimized antibiotic use on the rates of colonization with penicillin G-nonsusceptible Streptococcus pneumoniae (PNSP) in children. This study evaluates the effect of community-based intervention strategies on the prevalence of pnsp colonization. METHODS A controlled, population-based pharmacoepidemiological trial was conducted from January through May 2000. Three French geographic areas were selected on the basis of demographic similarities. Two intervention strategies were implemented: (1) reduced antibiotic use, which was achieved by not prescribing antibiotics for presumed viral respiratory tract infections (the prescription-reduction group); and (2) better adaptation of dose and duration (the dose/duration group). A control group received no intervention. The target population was children aged 3-6 years who were attending kindergarten. Oropharyngeal pneumococcus colonization and antibiotic use were monitored throughout the 5-month study. RESULTS The prescription-reduction, dose/duration, and control groups included 601, 483, and 405 children, respectively. The interventions induced significantly larger decreases in antibiotic use in the prescription-reduction group (-18.8%) and dose/duration group (-17.1%) than in the control group (-3.8%), and the rates of PNSP colonization were initially similar for the 3 groups (52.5%, 55.1%, and 50.0%, respectively). At the end of the 5-month study, the rates of PNSP colonization were 34.5% for the prescription-reduction group (P=.05) and 44.3% for the dose/duration group (P=.8), compared with 46.2% for the control group. CONCLUSIONS Intensive educational strategies aimed at optimizing antibiotic use can significantly reduce the rate of PNSP colonization in areas with high resistance rates.

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.

Pediatric Pneumococcal Serotypes in 4 European Countries

After heptavalent pneumococcal conjugate vaccine (PCV7) was marketed in France, Spain, Belgium, and England and Wales (United Kingdom), invasive disease from non-PCV7 serotypes (NVT) increased. Adjusted serotype-specific incidences among children <15 years of age were compared between 1999-2002 (prevaccine) and 2005-2006 (postmarketing). Vaccine coverage increased to approximately 32%-48% in France, Spain, and Belgium but remained <1% in England and Wales. Serotype 1 incidence rose in all age groups and countries (incidence rate ratio [IRR] 1.3-4.2; p<0.004), independently of PCV7 use, but incidence of serotypes 7F and 19A increased most in France, Spain, and Belgium (IRR 1.9-16.9 in children <5 years; p<0.001), where PCV7 coverage was greater. Vaccine-induced replacement of PCV7 serotypes possibly contributed to NVT increases, as did secular trends. New vaccines targeting these serotypes are available, but serotype dynamics needs further exploration that accounts for underreporting and prevaccine trends.

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.