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

OBJECTIVE: 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) <5 years of age. METHODS: 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. RESULTS: 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 4-5 years 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]). CONCLUSIONS: 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.

Carrier-Induced Hyporesponsiveness to Pneumococcal Conjugate Vaccines: Unraveling the Influence of Serotypes, Timing, and Previous Vaccine Dose.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) elicit lower immune response against serotypes carried before or at the time of vaccination (hyporesponsiveness) in infants. The limited studies conducted to date did not permit comprehensive insights regarding this phenomenon. This study, the largest ever conducted with both carriage and serologic endpoints, attempted to add insight on serotype-specific hyporesponsiveness in relation to the number of PCV doses administered before carriage acquisition. METHODS: In a double-blind randomized clinical trial (n = 1754 infants), 7-valent or 13-valent PCV was administered at ages 2, 4, 6, and 12 months. New acquisition was defined based on nasopharyngeal swabs at ages 2, 4, 6, 7, and 12 months. Serotype-specific immunoglobulin G levels were obtained 1 month after the infant series and 1 month after the toddler dose. RESULTS: A lower immune response after the infant series and the toddler dose was consistently observed for carriers of serotypes 6A, 6B, 18C, and 19F at predefined time points, with a similar trend observed in carriers of serotype 23F. In contrast, carriage of serotypes 9V, 14, and 19A did not generally affect immune responses. For some but not all serotypes, hyporesponsiveness was decreased with an increased number of vaccine doses received before acquisition. A complex interrelationship between carriage and immune response was observed between cross-reacting serotypes. CONCLUSIONS: Carrier-induced hyporesponsiveness to PCVs is common, differs among serotypes, and depends on timing of carriage acquisition and prior number of administered PCV doses. CLINICAL TRIALS REGISTRATION: NCT00508742.

Dose-specific Effectiveness of 7- and 13-Valent Pneumococcal Conjugate Vaccines Against Vaccine-serotype Streptococcus pneumoniae Colonization in Children.

BACKGROUND: Reduced-dose pneumococcal conjugate vaccine (PCV) schedules are under consideration in countries where children are recommended to receive 3 doses. Whereas PCV-derived protection against vaccine-serotype colonization is responsible for herd effects of vaccination, dose-specific PCV effectiveness against colonization endpoints is not known. We aimed to assess the performance of differing PCV schedules against vaccine-serotype colonization in children. METHODS: From 2009-2016, we monitored pneumococcal carriage in southern Israel, where children should receive PCV at ages 2 months, 4 months, and 12 months (2 primary [p] +1 booster [b] schedule). We analyzed nasopharyngeal swabs and vaccination histories from 5928 children aged 0-59 months without symptoms of diseases potentially attributable to pneumococci. Matching individuals on age, sex, ethnicity, visit timing, and recent antibiotic receipt, we measured schedule-specific 7-valent PCV (PCV7) and 13-valent PCV (PCV13) effectiveness against vaccine-serotype colonization in a modified case-control framework. We sampled from the distribution of all possible case-control match assignments for statistical analyses. RESULTS: Receiving 2 primary-series PCV13 doses conferred 53% (95% confidence interval [CI], 32-67%) protection against PCV13-serotype colonization at ages ≤12 months; 1 primary-series dose was not protective. A 2p+1b PCV13 series conferred 40% (95% CI, 4-67%) and 62% (95% CI, 33-83%) protection against PCV13-serotype colonization at ages 13-24 months and 25-59 months, respectively. Estimates suggested greater PCV13-conferred protection against PCV7-targeted serotypes than the 6 PCV13-only serotypes. As compared to children receiving 2p+1b PCV13 dosing, those receiving 1p+1b and 2p+0b schedules experienced 2.05-fold (95% CI, 1.12-5.00) and 3.33-fold (95% CI, 2.28-4.93) greater odds, respectively, of vaccine-serotype pneumococcal colonization at ages 13-24 months. CONCLUSIONS: Our results demonstrate real-world effectiveness of 2p+1b PCV dosing against vaccine-serotype colonization. Reduced-dose schedules may confer lower protection against vaccine-serotype carriage during and beyond the first year of life.

Infants Receiving a Single Dose of Nirsevimab to Prevent RSV Do Not Have Evidence of Enhanced Disease in Their Second RSV Season.

To characterize nirsevimab in the prevention of RSV, children from the Phase 3 MELODY trial were followed through their second RSV season. No increase in medically attended RSV lower respiratory tract infections or evidence of antibody-dependent enhancement of infection or disease severity was found for nirsevimab vs placebo recipients. Clinical Trial Registration: Clinicaltrials.gov, NCT03979313, https://clinicaltrials.gov/ct2/show/NCT03979313.

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

OBJECTIVES: Following 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. METHODS: Computerized 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. RESULTS: A 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. CONCLUSIONS: In 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.

Effect of reduced two-dose (1+1) schedule of 10 and 13-valent pneumococcal conjugate vaccines (SynflorixTM and Prevenar13TM)) on nasopharyngeal carriage and serotype-specific immune response in the first two years of life: Results from an open-labelled randomized controlled trial in Indian children.

INTRODUCTION: This study aimed to assess the effect of a reduced dose regime (1 + 1) of PCV10 and PCV13 along with 3-dose regimes on pneumococcal vaccine-type (VT) carriage and immunogenicity in the first two years of life in PCV-naïve Indian children. METHODS: A total of 805 healthy infants aged 6-8 weeks were randomised to 7 groups (n = 115). Six groups received SynflorixTM(PCV10) or Prevenar13TM(PCV13) in the following schedules: 3 + 0 (three primary at 6, 10, and 14 weeks); 2 + 1 (two primary 6 and 14 weeks with booster at 9 months; 1 + 1 (one primary at 14 weeks with booster at 9 months). The 7th group was a PCV-naïve control group. Nasopharyngeal swabs were collected at 6, 18 weeks, 9, 10, 15, and 18 months of age. Venous blood samples were collected at 18 weeks, 9, 10, and 18 months of age for assessment of sero-specific IgG antibodies. Additionally, functional activity using a serotype specific opsonophagocytic assay (OPA) was assessed at 10 and 18 months of age in a subset (20%) of participants. RESULTS: All schedules of PCV13 showed significant 13VT carriage reduction in the second year of life as compared to control. At 15 months of age, PCV13 (1 + 1) showed 45 % reduction in 13VT-carriage compared to the control [OR = 0.55 (95% CI; 0.31-0.97), p= 0.038]. None of the PCV10 schedules showed significant reduction in 10VT carriage in the second year. Although not powered for these outcomes, at 18 months of age, 1 + 1 and 2 + 1 schedules of both vaccines demonstrated higher sero-responders for all serotypes, higher geometric mean concentrations (GMC) for all serotypes except 23F [with both vaccines], higher percent OPA responders and OPA geometric mean titres (GMT) compared to the 3 + 0 schedules for all serotypes. CONCLUSION: The reduced dose schedule (1 + 1) of PCV13 results in significant VT-carriage reduction in the second year of life. Immune protection provided by 1 + 1 schedules of PCV10 and PCV13 in the second year of life is comparable to WHO-recommended 3-dose schedules.

Pneumonia vaccines for all who need them.

The UN's Millennium Development Goal 4 aims for a two-thirds reduction in deaths among children under five by 2015. With pneumonia being the number one killer of children under five,(1) this can only be achieved if we prevent and protect children from pneumonia-related deaths-and that will take global commitment and investment in life-saving interventions, like vaccines.

Prevention of early episodes of otitis media by pneumococcal vaccines might reduce progression to complex disease.

Otitis media is a common childhood infection of the middle ear and a major cause of morbidity. This multifactorial disease manifests as a spectrum of clinical syndromes from uncomplicated acute otitis media to more complex recurrent and chronic cases (frequently polymicrobial), with the major pathogens involved being Streptococcus pneumoniae and non-typeable Haemophilus influenzae. Pneumococcal conjugate vaccines (PCVs) target only a few serotypes that cause otitis media; however, results from studies suggest that existing PCVs can prevent early episodes of disease associated with vaccine serotypes, resulting in a reduction of subsequent complex cases caused by non-vaccine serotypes and other otopathogens, which contribute considerably to the disease burden. In this Review, we discuss the role of pneumococcus in the disease continuum and assess clinical evidence showing the effect of prevention of early episodes on the complex interplay between bacterial species implicated in otitis media.

Accurate diagnosis and appropriate treatment of acute bacterial rhinosinusitis: minimizing bacterial resistance.

BACKGROUND: Antimicrobial resistance in respiratory pathogens has become a common clinical problem that has serious public health implications. Inappropriate use of antibiotics for the treatment of viral upper respiratory tract infections (URTIs) has contributed to the development of resistant microorganisms. Health care providers can help control the spread of resistance by limiting the use of antimicrobial agents to infections that meet clinical guidelines for a bacterial cause. OBJECTIVE: This article examines the means of accurately diagnosing and appropriately treating acute bacterial rhinosinusitis (ABRS) in an effort to control increasing levels of resistance. METHODS: This article discusses current treatment guidelines that provide the evidenced-based rationale for choosing the most appropriate antimicrobial agents for suspected ABRS in adults and children. An evidence-based approach can help minimize the public health threat posed by the continuing increase in microbial resistance. RESULTS: Although definitive clinical criteria that differentiate between ABRS and viral URTI are lacking, careful evaluation of the duration and severity of symptoms provides a rational basis for diagnosing ABRS in primary care settings. CONCLUSIONS: Once a diagnosis of ABRS has been made, empiric antibiotic therapy may be justified. When it is, the first-line agent should be the narrowest spectrum antibiotic that would be expected to eradicate the most common causative organisms. The antibiotic selection process should take into account prevailing patterns of resistance and the presence of risk factors for infection with resistant pathogens, as well as published evidence-based guidelines.

The fundamental link between pneumococcal carriage and disease.

Streptococcus pneumoniae (pneumococcus) is a major cause of worldwide mortality and morbidity, and to a large extent is vaccine-preventable. Nasopharyngeal carriage of pneumococcus precedes disease and is the source of pneumococcal spread between people. The use of vaccine effect on carriage as part of the vaccine licensure and post-vaccine introduction evaluation could facilitate and expand the licensure of new, life-saving pneumococcal vaccines and enable a comprehensive estimate of population effects after vaccine introduction. The authors provide a review of the evidence supporting pneumococcal carriage at the individual level as an immediate and necessary precursor to pneumococcal disease. Based on such a causal link between carriage and disease, the authors emphasize the role of information on pneumococcal carriage in vaccine trials and in public health decision-making.

Vigilancia epidemiológica prospectiva de la enfermedad neumocócica invasora y de la neumonía en niños de San José, Costa Rica / Prospective epidemiologic surveillance of invasive pneumoccal disease and pneumonia in children in San Jos‚, Costa Rica

Justificación y objetivo: Streptococcus pneumoniae es globalmente la primera causa de muertes inmunoprevenibles en niños menores de 5 años. Métodos: entre 2007 y 2009 se realizó una vigilancia prospectiva con base poblacional en niños de 28 días a 36 meses en San José, Costa Rica. Se determinaron la incidencia de la enfermedad neumocócica invasora y de neumonía confirmada clínicamente y por radiografía, la distribución de serotipos y la sensibilidad a los antibióticos. Resultados: participaron 8801 sujetos (mediana de edad: 13,0 meses). En 25 niños se detectó enfermedad neumocócica invasora mediante aislamiento en cultivos (22) o mediante reacción de polimerasa en cadena y un cuadro clínico compatible con enfermedad neumocócica invasora. En los casos diagnosticados únicamente por cultivo, la tasa de incidencia de enfermedad neumocócica invasora en niños de 28 días a 36 meses de edad fue de 33,7/100000 por año para los años 1 y 2 combinados. Al considerar los casos adicionales diagnosticados por reacción de polimerasa en cadena, la incidencia aumnetó a 46,/100 000. El serotipo más frecuente fue el 14 (28,6 por ciento), seguido por los serotipos 3, 4, 6A, 19A, 22F. 42,9 por ciento de los aislamientos eran insensibles a la penicilina y al cotrimoxazol. La incidencia de neumonía confirmada clínicamente y de neumonía confirmada por radiografía fue de 1968/100 000 y 551/100 000, respectivamente. Conclusión: la incidencia de enfermedad neumocócica invasora y neumonía en niños de San José es considerable. Estos datos epidemiológicos sirven como línea de base para evaluar la efectividad de nuevas vacunas antineumocócicas conjugadas.

The potential indirect effect of conjugate pneumococcal vaccines.

Pneumococcal conjugate vaccines are highly effective in preventing invasive disease in infants and young children, with favorable safety and immunogenicity profiles. These pediatric vaccines have also shown efficacy in reducing cases of non-invasive disease (i.e. otitis media, pneumonia). Recently, pneumococcal conjugate vaccines have demonstrated additional protective qualities that may enhance their use worldwide. For example, they can reduce nasopharyngeal acquisition of vaccine-specific serotypes of Streptococcus pneumoniae, which may in turn reduce the incidence of pneumococcal disease among non-vaccinated individuals; this is termed indirect or herd immunity. Although the emergence of antibiotic-resistant strains has complicated disease management, pneumococcal conjugate vaccines have been shown to protect against pneumococcal disease caused by such strains because most antibiotic-resistant strains are of the serotypes included in these vaccines. Thus, widespread use of these conjugate vaccines may prevent disease by providing both direct and indirect immunity, and may reduce the use of antibiotics and the development of antibiotic resistance worldwide.