Pneumococcal Conjugate Vaccine Implementation Research Articles

High diversity within and low but significant genetic differentiation among geographic and temporal populations of the global Streptococcus pneumoniae.

Streptococcus pneumoniae is the major cause of invasive pneumococcal disease. However, the global population structure remains largely unexplored. In this study, we investigated the spatial and temporal patterns of genetic variation of S. pneumoniae based on archived multilocus sequence typing data from PubMLST.org. Our analyses demonstrated both shared and unique distributions of sequence types (STs) and allele types among regional populations. Among the 17 915 global STs, 36 representing 15 263 isolates were broadly shared among all six continents, consistent with recent clonal dispersal and expansion of this pathogen. The analysis of molecular variance revealed that>96% genetic variations were found within individual regional populations. However, though low (<4%), statistically significant genetic differentiation among regional populations was observed. Comparisons between non-clone-corrected and clone-corrected datasets showed that localized clonal expansion contributed significantly to the observed genetic differentiations among regions. Temporal analyses of the isolates showed that implementation of pneumococcal conjugate vaccine impacted the distributions of STs, but the effect on population structure was relatively limited. Linkage disequilibrium analyses identified evidence for recombination in all continental populations; however, the inferred recombination was not random. We discussed the limitations and implications of our analyses to the global epidemiology and future vaccine developments for S. pneumoniae.

Reducing the equity gap in under-5 mortality through an innovative community health program in Ethiopia: an implementation research study

BackgroundThe Ethiopian government implemented a national community health program, the Health Extension Program (HEP), to provide community-based health services to address persisting access-related barriers to care using health extension workers (HEWs). We used implementation research to understand how Ethiopia leveraged the HEP to widely implement evidence-based interventions (EBIs) known to reduce under-5 mortality (U5M) and address health inequities.MethodsThis study was part of a six-country case study series using implementation research to understand how countries implemented EBIs between 2000–2015. Our mixed-methods research was informed by a hybrid implementation science framework using desk review of published and gray literature, analysis of existing data sources, and 11 key informant interviews. We used implementation of pneumococcal conjugate vaccine (PCV-10) and integrated community case management (iCCM) to illustrate Ethiopia’s ability to rapidly integrate interventions into existing systems at a national level through leveraging the HEP and other implementation strategies and contextual factors which influenced implementation outcomes.ResultsEthiopia implemented numerous EBIs known to address leading causes of U5M, leveraging the HEP as a platform for delivery to successfully introduce and scale new EBIs nationally. By 2014/15, estimated coverage of three doses of PCV-10 was at 76%, with high acceptability (nearly 100%) of vaccines in the community. Between 2000 and 2015, we found evidence of improved care-seeking; coverage of oral rehydration solution for treatment of diarrhea, a service included in iCCM, doubled over this period. HEWs made health services more accessible to rural and pastoralist communities, which account for over 80% of the population, with previously low access, a contextual factor that had been a barrier to high coverage of interventions.ConclusionsLeveraging the HEP as a platform for service delivery allowed Ethiopia to successfully introduce and scale existing and new EBIs nationally, improving feasibility and reach of introduction and scale-up of interventions. Additional efforts are required to reduce the equity gap in coverage of EBIs including PCV-10 and iCCM among pastoralist and rural communities. As other countries continue to work towards reducing U5M, Ethiopia’s experience provides important lessons in effectively delivering key EBIs in the presence of challenging contextual factors.

Antimicrobial Resistance in Streptococcus pneumoniae before and after the Introduction of Pneumococcal Conjugate Vaccines in Brazil: A Systematic Review.

Streptococcus pneumoniae causes serious illnesses, such as pneumonia, bacteremia, and meningitis, mainly in immunocompromised individuals and those of extreme ages. Currently, pneumococcal conjugate vaccines (PCVs) are the best allies against pneumococcal diseases. In Brazil, the 10-valent and 13-valent PCVs have been available since 2010, but the threat of antimicrobial resistance persists and has been changing over time. We conducted a systematic review of the literature with works published since 2000, generating a parallel between susceptibility data on isolates recovered from colonization and invasive diseases before and after the implementation of PCVs for routine childhood use in Brazil. This systematic review was based on the Cochrane Handbook for Systematic Reviews of Interventions and Preferred Reporting Items for Systematic Literature Reviews and Meta-Analyses (PRISMA) guidelines. Despite the inclusion of PCVs at a large scale in the national territory, high frequencies of non-susceptibility to important drugs used in pneumococcal diseases are still observed, especially penicillin, as well as increasing resistance to macrolides. However, there are still drugs for which pneumococci have a comprehensive sensitivity profile.

Effect of 13-valent pneumococcal conjugate vaccine on experimental carriage of Streptococcus pneumoniae serotype 6B in Blantyre, Malawi: a randomised controlled trial and controlled human infection study

The effect of childhood pneumococcal conjugate vaccine implementation in Malawi is threatened by absence of herd effect. There is persistent vaccine-type pneumococcal carriage in both vaccinated children and the wider community. We aimed to use a human infection study to measure 13-valent pneumococcal conjugate vaccine (PCV13) efficacy against pneumococcal carriage. We did a double-blind, parallel-arm, randomised controlled trial investigating the efficacy of PCV13 or placebo against experimental pneumococcal carriage of Streptococcus pneumoniae serotype 6B (strain BHN418) among healthy adults (aged 18-40 years) from Blantyre, Malawi. We randomly assigned participants (1:1) to receive PCV13 or placebo. PCV13 and placebo doses were prepared by an unmasked pharmacist to maintain research team and participant masking with identification only by a randomisation identification number and barcode. 4 weeks after receiving either PCV13 or placebo, participants were challenged with 20 000 colony forming units (CFUs) per naris, 80 000 CFUs per naris, or 160 000 CFUs per naris by intranasal inoculation. The primary endpoint was experimental pneumococcal carriage, established by culture of nasal wash at 2, 7, and 14 days. Vaccine efficacy was estimated per protocol by means of a log-binomial model adjusting for inoculation dose. The trial is registered with the Pan African Clinical Trials Registry, PACTR202008503507113, and is now closed. Recruitment commenced on April 27, 2021 and the final visit was completed on Sept 12, 2022. 204 participants completed the study protocol (98 PCV13, 106 placebo). There were lower carriage rates in the vaccine group at all three inoculation doses (0 of 21 vs two [11%] of 19 at 20 000 CFUs per naris; six [18%] of 33 vs 12 [29%] of 41 at 80 000 CFUs per naris, and four [9%] of 44 vs 16 [35%] of 46 at 160 000 CFUs per naris). The overall carriage rate was lower in the vaccine group compared with the placebo group (ten [10%] of 98 vs 30 [28%] of 106; Fisher's p value=0·0013) and the vaccine efficacy against carriage was estimated at 62·4% (95% CI 27·7-80·4). There were no severe adverse events related to vaccination or inoculation of pneumococci. This is, to our knowledge, the first human challenge study to test the efficacy of a pneumococcal vaccine against pneumococcal carriage in Africa, which can now be used to establish vaccine-induced correlates of protection and compare alternative strategies to prevent pneumococcal carriage. This powerful tool could lead to new means to enhance reduction in pneumococcal carriage after vaccination. Wellcome Trust.

Dynamics of Pediatric Antibiotic Use Differ between High- and Low-Prescribing Clinics after Pneumococcal Conjugate Vaccines

To compare dispensed oral antibiotic prescription rates (DAPRs) after implementation of pneumococcal conjugate vaccine (PCV) in high antibiotic-prescribing clinics (HPC) with low antibiotic-prescribing clinics (LPC) in 2 distinct ethnic groups of children (Jewish and Bedouin children)<5years of age. Clinics with ≥50 insured children, active both pre-PCV (2005-2009) and post-PCV (2010-2018) implementation, were included. HPC and LPC were defined by DAPRs above or below the median in each age and ethnic group. Monthly dispensed antibiotic prescription rate (DAPR) trends (adjusted for age and ethnicity) were calculated using interrupted time series. Mean yearly incidence rate-ratios (late PCV13 vs pre-PCV) were calculated. Bedouin HPC had the highest pre-PCV overall-DAPR per 1000 child-years± SD (2520.4 ± 121.2), followed by Jewish HPC (1885.5 ± 47.6), Bedouin LPC (1314.8 ± 81.6), and Jewish LPC (996.0 ± 19.6). Shortly after PCV implementation, all DAPRs and amoxicillin/amoxicillin-clavulanate DAPRs declined in all groups except Jewish LPC, stabilizing within 4-5years post-PCV. The rates and magnitudes of declines were directly proportional to the pre-PCV DAPR magnitudes, achieving near-complete closure of the pre-PCV DAPR gaps between the 4 groups (rates during late-PCV13 ranging from 1649.4 ± 23.5 [Bedouin HPC] to 1200.3 ± 72.4 [Jewish LPC]). PCVs are a powerful tool in reducing outpatient antibiotic consumption among young children, especially in HPC, resulting in partial closure of DAPR gap between HPC and LPC. The higher impact on HPC suggests that PCV-associated declines of respiratory disease may strongly contribute to a judicious antibiotic approach in clinics with high antibiotic consumption.

The impact of pneumococcal conjugate vaccine on ceftriaxone consumption in the community among young children

ObjectivesFollowing pneumococcal conjugate vaccine (PCV) introduction, community pediatric dispensed prescription rates (DPR) of oral antibiotics declined, in parallel to respiratory tract infection (RTI). We assessed the dynamics of outpatient parenteral ceftriaxone DPR. MethodsComputerized data for children <5 years were examined during 13 years (including 4 pre-PCV years). DPR from clinics with ≥50 insured children, active both before and after PCV implementation were included. Interrupted time series with segmented regression stratified by age and ethnicity, and adjusted for seasonality was applied to show monthly DPR trends. ResultsA total of 29,226 prescriptions were dispensed. No significant trends in ceftriaxone DPR were seen pre-PCV. Shortly after PCV implementation, DPR abruptly and significantly declined, stabilizing in late-PCV period (5 years postimplementation). The dynamics were compared between the two ethnic groups in the region, Jewish and Bedouin children (the latter with higher crowding and respiratory disease rates). Among Jewish children, ceftriaxone was mainly dispensed during winter vs no seasonality among Bedouin children. ConclusionsIn southern Israel, outpatient ceftriaxone DPR declined post-PCV in young children, similar to the trends of RTIs and oral antibiotic prescriptions, suggesting a causative role of PCVs. The differences between the two ethnic groups suggest possible involvement of additional factors.

Estimating the Global and Regional Burden of Streptococcus pneumoniae Meningitis in Children: Protocol for a Systematic Review and Meta-Analysis.

Streptococcus pneumoniae (Spn) has been a leading cause of bacterial meningitis in children. The most recent estimation of the global burden of Spn meningitis indicates a positive trajectory in eliminating Spn through the implementation of pneumococcal conjugate vaccines. However, continuous monitoring and assessment of the disease burden are necessary due to the evidence of serotype replacement, antibiotic resistance, and the impact of the recent COVID-19 pandemic. The aim of this systematic review is to provide an updated and focused assessment of the global and regional burden of Spn meningitis in children, which can guide policies and strategies to reduce the disease burden. Population-based studies published from January 1, 2000, to January 1, 2022, were preliminarily searched from the electronic databases PubMed, Embase, Global Health (CABI), and CINAHL Plus without any language restrictions. Studies were included if they reported the incidence, prevalence, mortality, or case-fatality ratio (CFR) for Spn meningitis in children aged 0-4 years; meningitis was confirmed by cerebrospinal fluid culture; the study period was a minimum of 1 year; the number of reported cases was at least 10; and the study had no methodological ambiguities. The article screening process follows the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. Characteristics including study period, setting, World Health Organization region, income level, vaccination information, and participant data (age, number of cases, deaths, sequelae, and risk factors) will be extracted from the included studies. Search results will be updated and incorporated into our review prior to finalizing the extraction of data. Generalized linear mixed models meta-analysis will be performed to estimate the pooled incidence and CFR. We will further assess the risk of bias and heterogeneity, and will perform subgroup and sensitivity analyses to provide a meaningful interpretation of the current burden and literature for pneumococcal meningitis. Our preliminary search in December 2021 yielded 9295 articles. Out of 275 studies that were assessed with our eligibility criteria, 117 articles were included. Data extraction and analysis are expected to be complete by January 2025. We plan to publish the results from the full study, including an updated search in 2024, by March 2025. Given that the major burden of Spn meningitis affects children under the age of 5 years, this systematic review will provide a thorough understanding of the global burden of Spn meningitis in this vulnerable population over a span of 2 decades. Insights into incidence trends, geospatial distribution, risk factors, and sequelae will be valuable for stakeholders, policy makers, and the academic community. This information will aid in the ongoing monitoring of the disease and in enhancing targeted vaccine programs to further mitigate the impact of the disease on children worldwide. PROSPERO CRD42021293110; https://tinyurl.com/kc3j5k4m. DERR1-10.2196/50678.

Dynamics of Antibiotic Resistance of Streptococcus pneumoniae in France: A Pediatric Prospective Nasopharyngeal Carriage Study from 2001 to 2022

Epidemiological surveillance of nasopharyngeal pneumococcal carriage is important for monitoring serotype distribution and antibiotic resistance, particularly before and after the implementation of pneumococcal conjugate vaccines (PCVs). With a prospective surveillance study in France, we aimed to analyze the dynamics of pneumococcal carriage, antibiotic susceptibility and serotype distribution in children aged 6 to 24 months who had acute otitis media between 2001 and 2022 with a focus on the late PCV13 period from May 2014 to July 2022. Trends were analyzed with segmented linear regression with autoregressive error. For the 17,136 children enrolled, overall pneumococcal carriage was stable during the study. During the late PCV13 period, the five most frequent serotypes were all non-PCV13 serotypes: 15B/C (14.3%), 23B (11.0%), 11A (9.6%), 15A (7.4%) and 35B (6.5%). During the same period, we observed a rebound of penicillin non-susceptibility (+0.15% per month, 95% confidence interval, +0.08 to 0.22, p &lt; 0.001). Five serotypes accounted for 64.4% of the penicillin non-susceptible strains: 11A (17.5%), 35B (14.9%), 15A (13.9%), 15B/C (9.9%) and 19F (8.2%); non-PCV13/PCV15 accounted for &lt;1%, and non-PCV15/PCV20 accounted for 28%. The next generation PCVs, particularly PCV20, may disrupt nasopharyngeal carriage and contribute to decreasing the rate of antibiotic resistance among pneumococci.

Prevention of pneumococcal diseases: the challenge remains

Streptococcus pneumoniae (pneumococcus) is a leading cause of pneumonia that kills almost a million children worldwide annually, mostly in African and Asian countries.1 By 2015, 129 countries have introduced pneumococcal conjugate vaccines (PCVs) that have substantially reduced child morbidity and mortality.2 However, post-vaccine surveillance has shown the emergence of diseases caused by non-vaccine serotypes as well as serotype replacement in nasopharyngeal colonisation.3 Although an impact of vaccination on invasive pneumococcal disease has been observed in young children (particularly those younger than 2 years, even after many years of pneumococcal conjugate vaccine implementation) the emergence of non-vaccine serotypes with antibiotic resistance has become a new global threat to the control and prevention of pneumococcal diseases.

Epidemiology of pediatric parapneumonic pleural effusion during 13-valent pneumococcal conjugate vaccine implementation

IntroductionThe reported incidence of parapneumonic pleural effusion, including empyema, has shown fluctuations in the last decades. It has been related to the implementation of different types of conjugate pneumococcal vaccines. MethodsWe have retrospectively reviewed data from all 10 public hospitals in Alicante Province (Spain) covering a population of 279,000 children under 15 years of age, between 2010 and 2018. Effusions less than 10 mm (PE−) and those of 10 mm or more (PE+) were separated. ResultsA total of 366 episodes of parapneumonic pleural effusion have been analyzed, 178 PE− (48.6%) and 188 PE+ (51.4%), with a median age of 4 years (interquartile range: 2–7 years) and marked seasonality with the maximum in winter and the minimum in summer. A culture proven bacterial agent was identified in 34 patients (9.3%), mainly Streptococcus pneumoniae (24 patients) followed by Streptococcus pyogenes (7 patients). The most frequent S. pneumoniae serotype was 19A (6 patients) and 3 vaccine failures were observed. The mean annual incidence rate was 14.3 cases per 100,000 children under 15 years of age (7.0 for PE− and 7.3 for PE+). No significant changes were observed in incidence over time, but noticeable differences in incidence were observed in different health departments. ConclusionsWe have not found temporal variations in incidence of parapneumonic effusion despite the implementation of the 13-valent pneumococcal conjugate vaccine. The unexplained disparity in incidence between close departments is noteworthy.

Clinical Presentations and Outcomes of Children in Canada With Recurrent Invasive Pneumococcal Disease From the IMPACT Surveillance Network.

Invasive pneumococcal disease due to Streptococcus pneumoniae can cause mortality and severe morbidity due to sepsis, meningitis and pneumonia, particularly in young children and the elderly. Recurrent invasive pneumococcal disease is rare yet serious sequelae of invasive pneumococcal disease that is associated with the immunocompromised and leads to a high mortality rate. This retrospective study reviewed recurrent invasive pneumococcal disease cases from the Canadian Immunization Monitoring Program, ACTive (IMPACT) between 1991 and 2019, an active network for surveillance of vaccine-preventable diseases and adverse events following immunization for children ages 0-16 years. Data were collected from 12 pediatric tertiary care hospitals across all 3 eras of public pneumococcal conjugate vaccine implementation in Canada. The survival rate within our cohort of 180 recurrent invasive pneumococcal disease cases was 98.3%. A decrease of 26.4% in recurrent invasive pneumococcal disease due to vaccine serotypes was observed with pneumococcal vaccine introduction. There was also a 69.0% increase in the rate of vaccination in children with preexisting medical conditions compared with their healthy peers. The decrease in recurrent invasive pneumococcal disease due to vaccine-covered serotypes has been offset by an increase of non-vaccine serotypes in this sample of Canadian children.

Clinical and Economic Burden of Pneumococcal Disease Due to Serotypes Contained in Current and Investigational Pneumococcal Conjugate Vaccines in Children Under Five Years of Age.

IntroductionThe widespread implementation of pneumococcal conjugate vaccines (PCVs) has significantly reduced the burden of pneumococcal disease around the world. Although licensed 10-valent (PCV10) and 13-valent (PCV13) vaccines have considerably reduced mortality and morbidity, a sizeable disease burden attributable to serotypes not contained in these PCVs remains. This study aimed to estimate the annual clinical and economic burden of pneumococcal disease attributable to licensed (PCV10 and PCV13) and investigational PCVs, notably 15-valent (PCV15) and 20-valent (PCV20) vaccines, in 13 countries in children under 5 years of age.MethodsA decision-analytic model was created to aggregate total cases [inclusive of invasive pneumococcal disease (IPD), pneumonia, and otitis media (OM)], deaths, and direct costs in each country of interest [stratified by PCV10/PCV13 countries, depending on national immunization programs (NIPs)] over 1 year, using up to the three most recent years of available serotype coverage data. Data inputs were sourced from local databases, surveillance reports, and published literature.ResultsIn 5 PCV10 NIPs (Austria, Finland, Netherlands, New Zealand, Sweden), most remaining PCV20-type disease was due to PCV13-unique serotypes (30–85%), followed by PCV20-unique (9–50%), PCV15-unique (4–15%), and PCV10-unique (2–14%) serotypes. In 8 PCV13 NIPs (Australia, Canada, France, Germany, Italy, South Korea, Spain, United Kingdom), most remaining PCV20-type disease was caused by PCV20-unique serotypes (16–69%), followed by PCV13-unique (11–54%), PCV15-unique (2–33%), and PCV10-unique serotypes (3–19%). Across all countries, PCV20 serotypes caused 3000 to 345,000 cases of disease and cost between $1.3 and $44.9 million USD annually with variability driven by population size, NIP status, and epidemiologic inputs. In aggregate, PCV20 serotypes caused 1,234,000 cases and $213.5 million in annual direct medical costs in children under 5 years of age.ConclusionDespite the success of PCV10 and PCV13 in reducing pneumococcal disease, a substantial clinical and economic burden remains due to serotypes contained in investigational vaccines.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-021-00544-1.

Association of Pneumococcal Serotype With Susceptibility to Antimicrobial Drugs: A Systematic Review and Meta-analysis.

Pneumococcal serotypes differ in antimicrobial susceptibility. However, patterns and causes of this variation are not comprehensively understood. We undertook a systematic review of epidemiologic studies of pneumococci isolated from carriage or invasive disease among children globally from 2000-2019. We evaluated associations of each serotype with nonsusceptibility to penicillin, macrolides, and trimethoprim/sulfamethoxazole. We evaluated differences in the prevalence of nonsusceptibility to major antibiotic classes across serotypes using random-effects meta-regression models and assessed changes in prevalence of nonsusceptibility after implementation of pneumococcal conjugate vaccines (PCVs). We also evaluated associations between biological characteristics of serotypes and their likelihood of nonsusceptibility to each drug. We included data from 129 studies representing 32 187 isolates across 52 countries. Within serotypes, the proportion of nonsusceptible isolates varied geographically and over time, in settings using and those not using PCVs. Factors predicting enhanced fitness of serotypes in colonization as well as enhanced pathogenicity were each associated with higher likelihood of nonsusceptibility to penicillin, macrolides, and trimethoprim/sulfamethoxazole. Increases in prevalence of nonsusceptibility following PCV implementation were evident among non-PCV serotypes, including 6A, 6C, 15A, 15B/C, 19A, and 35B; however, this pattern was not universally evident among non-PCV serotypes. Postvaccination increases in nonsusceptibility for serotypes 6A and 19A were attenuated in settings that implemented PCV13. In pneumococci, nonsusceptibility to penicillin, macrolides, and trimethoprim/sulfamethoxazole is associated with more frequent opportunities for antibiotic exposure during both prolonged carriage episodes and when serotypes cause disease. These findings suggest multiple pathways leading to resistance selection in pneumococci.

Decline in pneumococcal nasopharyngeal carriage in children 6–23 months with respiratory illnesses following pneumococcal conjugate vaccine implementation

BackgroundFollowing pneumococcal conjugate vaccines (PCVs) implementation, worldwide, pneumococcal carriage rates remained stable, indicating full replacement of vaccine-serotypes (VT) with non-VT. However, data are scarce regarding PCV impact on pneumococcal carriage rates in healthy vs. sick children. We assessed pneumococcal carriage rates dynamics in healthy and sick children 6–23 months, following PCV introduction. MethodsThis is a prospective, population-based surveillance conducted during the years 2009–2017, in southern Israel. Three groups were defined as follows: Children without respiratory infection signs (the healthy/non-respiratory group); Children who had a chest radiography at the hospital (the Hosp-CXR group); and children with community-acquired alveolar pneumonia (CAAP).Rate ratios (RRs; 95% CI) were calculated, comparing between late-13-valent PCV (PCV13) period (2016–2017) and early-PCV period (2009–2010). Rate ratios were adjusted for antibiotic administration, seasonality and ethnicity, and separate calculations were performed for 6–11 and 12–23 month old children. ResultsOverall, 51% of 8627 nasopharyngeal cultures were positive.In 2009–2010 (early-PCV period), the overall carriage rate was 55%; serotypes included in the PCV13 carriage rates were 28%, 31% and 38% in the healthy/non-respiratory, Hosp-CXR, and CAAP groups, respectively.Overall carriage rates in healthy/non-respiratory episodes were stable (~54%) when comparing between 2016 and 17 and 2009–10 (RR = 0.98; 0.84–1.15). In contrast, rates significantly declined for Hosp-CXR (RR = 0.78; 0.63–0.98) and CAAP (RR = 0.65; 0.47–0.89). These trends were driven by ~ 80% VT reductions, coupled with non-VT increase. ConclusionsFollowing 7-valent PCV/ PCV13 introduction, pneumococcal carriage rates declined in respiratory diseases, but not in healthy children and children without respiratory infections. These trends suggest that a reduction in pneumococcal carriage rates during respiratory infections indicates a decline in respiratory infections caused by VT, while carriage rates in non-respiratory cases reflect non-VT predominance, that have low disease potential for respiratory disease.

Impact of pneumococcal conjugate vaccines on healthcare utilization and direct costs for otitis media in children ≤2 years of age in two Swedish regions

ABSTRACT In Sweden, the 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in 2009 and replaced by the pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) or the 13-valent PCV (PCV13) from late 2009. We assessed the impact of PCVs on rates of antibiotic prescribing, tympanostomy tube placement (TTP), and healthcare resource utilization and direct costs of physician-diagnosed otitis media/acute otitis media (OM) in children ≤2 years of age living in Skåne (PCV7 then PHiD-CV) or Västra Götalandsregionen (VGR; PCV7 then PCV13). Retrospective cohort study using linked patient-level data from national and regional (Skåne and VGR) healthcare databases in Sweden from July 1, 2005, to December 31, 2013 (NCT02742753). Descriptive time-series analyses showed antibiotic prescriptions and TTP incidence declined after PHiD-CV/PCV13 introduction versus the pre-PCV period. The annualized mean frequencies of antibiotic use, primary care visits, outpatient visits, TTP and myringotomy procedures all decreased after PHiD-CV/PCV13 compared with pre-PCV cohorts. Annualized mean total OM-associated healthcare costs decreased in the PCV7 versus pre-PCV cohorts by 20.0% in Skåne and 10.2% in VGR, and further declined in the PHiD-CV and PCV13 cohorts (20.7% and 15.3%, respectively, relative to the PCV7 cohort), although the duration of PCV7 use differed between regions. Decreases in adjusted annualized cost ratios between cohorts per child susceptible to OM were statistically significant after PCV7 introduction and again with either PHiD-CV or PCV13 introduction in both regions. Following sequential PCV introduction, OM-related healthcare utilization and associated costs decreased in the study regions in Sweden. PLAIN LANGUAGE SUMMARY What is the context? Otitis media is one of the most frequent reasons for healthcare visits and antibiotic use among young children. Although it is considered as a mild illness, the overall economic burden is substantial due to its high frequency. Otitis media can be caused by different bacteria including Streptococcus pneumoniae, which is also responsible for pneumonia and meningitis. Pneumococcal conjugate vaccines Prevenar (Pfizer Inc.), Synflorix (GSK), and Prevenar 13 (Pfizer Inc.) protect against pneumococcal diseases and reduce its occurrence. However, it is not known how the routine use of these vaccines may affect otitis media-related healthcare resources and costs. What is new? In this study, we assessed trends in rates of healthcare utilization and associated costs due to otitis media in young children before (2005–2008) and after (2009–2013) use of pneumococcal conjugate vaccines. The study was conducted in two Swedish regions; one used Prevenar then Synflorix, while the other used Prevenar then Prevenar 13. We found that compared to the period before pneumococcal conjugate vaccine implementation, the post-pneumococcal conjugate vaccine period was associated with: A decrease in otitis media-related antibiotic prescriptions and surgical procedures in both regions. A decrease in the annual frequency of otitis media related antibiotic use, primary care and outpatient visits, and surgical procedures. A significant reduction in otitis media-related healthcare costs in both regions. What is the impact on current thinking? The use of pneumococcal conjugate vaccines effectively reduces healthcare utilization and resources associated with otitis media. This indirect effect on the reduction of otitis media burden provides further benefit to the implementation of pneumococcal vaccination.

Nasopharyngeal carriage rates and serotype distribution of Streptococcus pneumoniae among school children with acute otitis media in Central Java, Indonesia.

Streptococcus pneumoniae is a common bacterial pathogen that causes acute otitis media (AOM) in children. In this study, we investigated nasopharyngeal carriage rates and serotype distributions of S. pneumoniae among school children with AOM in Banyumas Regency, Central Java, Indonesia, from 2018 to 2019. Nasopharyngeal swab specimens and demographic data were collected from 122 children between the ages of 6 and 12. The specimens were cultured for the identification of S. pneumoniae, and serotyping was performed using a sequential multiplex PCR assay. We found that the S. pneumoniae carriage rate was 73 % (89/122) among children with AOM. Serotypes 23A (11 %) and 6A/6B (10 %) were the most common serotypes among the 91 cultured S. pneumoniae strains, followed by 3 (8 %), 14 (7 %), 6C/6D (7 %), 11A/11D (6 %), 15B/15C (4 %) and 35 B (4 %). Moreover, 41 % of the strains could be covered by the 13-valent pneumococcal conjugate vaccine, PCV13. In conclusion, high nasopharyngeal carriage rates of S. pneumoniae were found in school children with AOM, with almost half of the strains being the vaccine-type. This finding provides a baseline for nasopharyngeal carriage of S. pneumoniae in school children with AOM and supports the implementation of pneumococcal conjugate vaccines in Indonesia.

Antimicrobial resistance in paediatric Streptococcus pneumoniae isolates amid global implementation of pneumococcal conjugate vaccines: a systematic review and meta-regression analysis

SummaryBackgroundPneumococcal diseases are a leading cause of morbidity and mortality among children globally, and the burden of these diseases might be worsened by antimicrobial resistance. To understand the effect of pneumococcal conjugate vaccine (PCV) deployment on antimicrobial resistance in pneumococci, we assessed the susceptibility of paediatric pneumococcal isolates to various antimicrobial drugs before and after PCV implementation.MethodsWe did a systematic review of studies reporting antimicrobial susceptibility profiles of paediatric pneumococcal isolates between 2000 and 2020 using PubMed and the Antimicrobial Testing Leadership and Surveillance database (ATLAS; Pfizer). Population-based studies of invasive pneumococcal disease or nasopharyngeal colonisation were eligible for inclusion. As primary outcome measures, we extracted the proportions of isolates that were non-susceptible or resistant to penicillin, macrolides, sulfamethoxazole–trimethoprim, third-generation cephalosporins, and tetracycline from each study. Where available, we also extracted data on pneumococcal serotypes. We estimated changes in the proportion of isolates with reduced susceptibility or resistance to each antibiotic class using random-effects meta-regression models, adjusting for study-level and region-level heterogeneity, as well as secular trends, invasive or colonising isolate source, and countries' per-capita gross domestic product.FindingsFrom 4910 studies screened for inclusion, we extracted data from 559 studies on 312 783 paediatric isolates. Susceptibility of isolates varied substantially across regions both before and after implementation of any PCV product. On average across all regions, we estimated significant absolute reductions in the proportions of pneumococci showing non-susceptibility to penicillin (11·5%, 95% CI 8·6–14·4), sulfamethoxazole–trimethoprim (9·7%, 4·3–15·2), and third-generation cephalosporins (7·5%, 3·1–11·9), over the 10 years after implementation of any PCV product, and absolute reductions in the proportions of pneumococci resistant to penicillin (7·3%, 5·3–9·4), sulfamethoxazole–trimethoprim (16·0%, 11·0–21·2), third-generation cephalosporins (4·5%, 0·3–8·7), macrolides (3·6%, 0·7–6·6) and tetracycline (2·0%, 0·3–3·7). We did not find evidence of changes in the proportion of isolates non-susceptible to macrolides or tetracycline after PCV implementation. Observed changes in penicillin non-susceptibility were driven, in part, by replacement of vaccine-targeted serotypes with non-vaccine serotypes that were less likely to be non-susceptible.InterpretationImplementation of PCVs has reduced the proportion of circulating pneumococci resistant to first-line antibiotic treatments for pneumonia. This effect merits consideration in assessments of vaccine impact and investments in coverage improvements.FundingBill & Melinda Gates Foundation.

Unraveling the Impact of Pneumococcal Conjugate Vaccines on Ambulatory Antibiotic Drug Consumption in Young Children: An Interrupted Time-Series Analysis.

Pneumococcal conjugate vaccines (PCVs) reduce respiratory infections in young children, the main antibiotic consumers. Following PCV implementation, dispensed antibiotic prescription (DAP) rates in young children were expected to decline. Computerized data on DAP for children <5 years were examined during a 13-year period (including 4 pre-PCV years). All DAPs from clinics with ≥50 insured children, active both pre- and post-PCV implementation were included. Interrupted time-series with segmented regression was applied to analyze monthly DAP rate trends, adjusted for age, ethnicity, and season. Incidence rate ratios (IRRs) of DAPs during the late PCV13 period versus 4 years pre-PCV were calculated both as absolute rate ratios (aIRRs) and relative to expected rates (rIRRs). Of 1 090 870 DAPs, 57% were in children <2 years. All-DAP rates peaked in the cold season. Post-PCV7/PCV13 implementation, all DAP rates abruptly and significantly declined, reaching a plateau within 5 years. This was largely driven by amoxicillin/amoxicillin-clavulanate (75% of DAPs). Age <2 years and Bedouin ethnicity were significantly associated with higher pre-PCV DAP rates but with faster and greater decline post-PCV, achieving near elimination of gaps between ages and ethnic groups. Overall reduction (95% CIs) in DAP rates per 1000 was estimated between aIRR (344.7 [370.9-358.4]) and rIRR (110.4 [96.9-123.7]) values. Shortly following PCV implementation, overall DAP rates showed an abrupt, steep decline, stabilizing within 5 years, in parallel to post-PCV respiratory infection trends previously described in this population, suggesting causality. The variable patterns of certain drug categories suggest additional influences beyond PCV.

Epidemiology, Nasopharyngeal Carriage, Serotype Prevalence, and Antibiotic Resistance of Streptococcus pneumoniae in Indonesia.

In Indonesia, pneumococcal disease represents a considerable public health concern; however, published data on the epidemiology, nasopharyngeal carriage, serotype prevalence, and antibiotic resistance of Streptococcus pneumoniae in this region are limited. Therefore, this article reviews the available data from a variety of sources and also summarizes pneumococcal conjugate vaccine implementation and recommendations in Indonesia and subsequent impact on pneumococcal disease. Regional pneumococcal vaccination recommendations in Asia were also reviewed. Studies showed that pneumococcal nasopharyngeal carriage prevalence in Indonesia was approximately 43% to 55% in healthy children aged less than 5 years, which varied by age group, region, and year. Serotype analysis of pneumococcal nasopharyngeal carriage isolates in Indonesia revealed that 38% to 60% of isolates would be covered by the 13-valent pneumococcal conjugate vaccine (PCV13). The antimicrobial resistance of pneumococcal disease has increased over time; between 1997 and 2012, resistance to penicillin and sulfamethoxazole increased from 0% to 28% and 9% to 62%, respectively. Inclusion of pneumococcal conjugate vaccines into immunization programs is being implemented gradually. In 2017, Indonesia implemented a regional PCV13 immunization program in Lombok with a 2 + 1 vaccination schedule that was expanded in 2018–2019 to West Nusa Tenggara and Bangka Belitung Provinces; this expansion is predicted to substantially reduce the burden of pneumococcal disease in Indonesia. Overall, the limited data available regarding pneumococcal disease in Indonesia highlight the unmet need for comprehensive disease surveillance studies in this region that can help direct vaccination strategies.

Invasive pneumococcal disease incidence in children and adults in France during the pneumococcal conjugate vaccine era: an interrupted time-series analysis of data from a 17-year national prospective surveillance study

The long-term benefits of pneumococcal conjugate vaccines (PCVs) remain unknown because of serotype replacement. We aimed to estimate the effect of PCV implementation on invasive pneumococcal disease incidence in France. We did a quasi-experimental interrupted time-series analysis using data from a French national prospective surveillance system. We included all invasive pneumococcal disease cases in children and adults from more than 250 participating hospitals between Jan 1, 2001, and Dec 31, 2017. The primary outcome was incidence of invasive pneumococcal disease (meningitis and non-meningitis) over time, analysed by segmented regression with autoregressive error. Isolates were serotyped by latex agglutination with antiserum samples. We included 75 903 patients with invasive pneumococcal disease, including 4302 (5·7%) children younger than 2 years and 37 534 (49·4%) adults aged 65 years or older. Before PCV7 implementation, the estimated monthly incidence of invasive pneumococcal disease was 0·78 cases per 100 000 inhabitants, which did not change significantly up to May, 2010. PCV13 implementation in 2010 was followed by a significant decrease in the incidence of invasive pneumococcal disease (-1·5% per month, 95% CI -2·2 to -0·8), reaching an estimated monthly incidence of 0·52 cases per 100 000 inhabitants in December, 2014. From January, 2015, the incidence rebounded (1·8% per month, 95% CI 1·0 to 2·6), reaching an estimated monthly incidence of 0·73 cases per 100 000 inhabitants in December, 2017. The estimated monthly incidence increased from 0·93 cases per 100 000 in December, 2014, to 1·73 cases per 100 000 in December, 2017, for children younger than 2 years, and from 1·54 cases per 100 000 in December, 2014, to 2·08 cases per 100 000 in December, 2017, for adults aged 65 years or older. The main non-PCV13 serotypes involved in the increase were 24F in young children and 12F, 22F, 9N, and 8 in adults aged 65 years or older. PCV13 implementation led to a major reduction in the incidence of invasive pneumococcal disease. However, a rebound in cases among children and adults since 2015, driven by several emerging non-PCV13 serotypes, jeopardises the long-term PCV benefits. These findings, if confirmed in the coming years, should be considered in the development of next-generation PCVs and might guide policy makers in the selection of future pneumococcal vaccines. Foundation for Medical Research; Pfizer, BioMérieux, Sanofi for the Regional Observatory of Pneumococci.