Application of pharmacokinetic/pharmacodynamic analysis to evaluate the adequacy of antimicrobial therapy for pediatric acute otitis media in Spain before and after the introduction of the PCV7 vaccine.

OBJECTIVE: To evaluate, by applying pharmacokinetic/pharmacodynamic (PK/PD) analysis, if the change in antibiotic susceptibility after the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in Spain had any influence on the usefulness of the antimicrobials more frequently used as empirical treatment of pediatric acute otitis media (AOM). METHODS: PK parameters and susceptibility of Streptococcus pneumoniae and Haemophilus influenzae were obtained from bibliography. Monte Carlo simulation was used to estimate the cumulative fraction of response (CFR), understood as the expected probability of therapy success. For amoxicillin and amoxicillin/clavulanate, the target was free antibiotic concentration remaining above the minimum inhibitory concentration (MIC) for ≥50% of the dosing interval (fT>MIC≥50%), whereas for cefuroxime axetil and cefotaxime, the target was fT>MIC≥60%. CFR values ≥90% were considered successful. RESULTS: When all serotypes of S. pneumoniae are considered, amoxicillin and cefotaxime turned out to reach a high probability of success, and difference before and after vaccination was scarce. For H. influenzae, CFR values were higher with amoxicillin/clavulanate than with amoxicillin. For both microorganisms, cefuroxime axetil resulted in low probability of success in the two periods of study. CONCLUSIONS: We have shown that the introduction of the PCV7 vaccination did not lead to changes in the probability of success of the current empiric treatments of the AOM. Integrated PK/PD analysis has demonstrated to be a useful tool to identify changes in antimicrobial activity after the implantation of a vaccination program, providing complementary information to the simple assessment of MIC values.

Retrospective cost-effectiveness of the 23-valent pneumococcal polysaccharide vaccination program in Australia.

BACKGROUND: The Australian infant pneumococcal vaccination program was funded in 2005 using the 7-valent pneumococcal conjugate vaccine (PCV7) and the 13-valent conjugate vaccine (PCV13) in 2011. The PCV7 and PCV13 programs resulted in herd immunity effects across all age-groups, including older adults. Coincident with the introduction of the PCV7 program in 2005, 23-valent pneumococcal polysaccharide vaccine (PPV23) was funded for all Australian adults aged over 65 years. METHODS: A multi-cohort Markov model with a cycle length of one year was developed to retrospectively evaluate the cost-effectiveness of the PPV23 immunisation program from 2005 to 2015. The analysis was performed from the healthcare system perspective with costs and quality-adjusted life years discounted at 5% annually. The incremental cost-effectiveness ratio (ICER) for PPV23 doses provided from 2005 to 2015 was calculated separately for each year when compared to no vaccination. Parameter uncertainty was explored using deterministic and probabilistic sensitivity analysis. RESULTS: It was estimated that PPV23 doses given out over the 11-year period from 2005 to 2015 prevented 771 hospitalisations and 99 deaths from invasive pneumococcal disease (IPD). However, the estimated IPD cases and deaths prevented by PPV23 declined by more than 50% over this period (e.g. from 12.9 deaths for doses given out in 2005 to 6.1 in 2015), likely driven by herd effects from infant PCV programs. The estimated ICER over the period 2005 to 2015 was approximately A$224,000/QALY gained compared to no vaccination. When examined per year, the ICER for each individual year worsened from $140,000/QALY in 2005 to $238,000/QALY in 2011 to $286,000/QALY in 2015. CONCLUSION: The cost-effectiveness of the PPV23 program in older Australians was estimated to have worsened over time. It is unlikely to have been cost-effective, unless PPV23 provided protection against non-invasive pneumococcal pneumonia and/or a low vaccine price was negotiated. A key policy priority should be to review of the future use of PPV23 in Australia, which is likely to be more cost-effective in certain high-risk groups.

Influence of pneumococcal conjugate vaccines on acute otitis media in Japan.

OBJECTIVE: This study investigated: (i) changes in the incidence of acute otitis media (AOM) following introduction of public funding for free inoculation with 7- and 13-valent pneumococcal conjugate vaccines (PCV7 and PCV13, respectively) and (ii) changes in the rate of myringotomies for AOM (MyfA) in children 1year following the publication of the first edition of the clinical practice guidelines for the diagnosis and management of AOM in children in Japan. METHODS: PCV7 was launched on the Japanese market in 2010 and gained public funding in 2011. PCV7 was replaced with PCV13 in November 2013. Using the Japan Medical Data Center Claims Database, an 11-year study conducted between January 2005 and December 2015 investigated the decline in the incidence of visits to medical institutions (VtMI) due to all-cause AOM in children <15years. The rate of MyfA from January 2007 to December 2015was also investigated and changes before and after introduction of public funding for PCV7 (pfPCV7) and PCV13 (pfPCV13) for children were examined. Statistical data for the age group between 10 years and <15years served as the control. An analysis was conducted to examine changes for each age group, from infants that had received PCVs to children <5years. Statistical analysis was performed using the chi-square test and Ryan's multiple comparison tests. Ryan's multiple comparison tests were applied at a 5% level of significance. Due to significant changes in the guidelines on the indications for myringotomy introduced in 2013, statistical analysis of the rate of MyfA was limited to the pre- and post-PCV7 period. RESULTS: After introduction of pfPCV7 and pfPCV13, no significant suppression of the incidence of VtMI was observed in any age group. There was a gradual decline in the rate of MyfA after 2011. Compared to the control group, significant differences in all age groups from infants to children <5years were observed (p<0.009, chi-square test). Within 2 years after the introduction of PCV7, a significant decline in the rate of MyfA was observed in 1- and 5-year-olds using Ryan's multiple comparison tests at a 5% level of significance. CONCLUSION: The preventative effect of PCVs on AOM was not established in this study. There was, however, a significant decline in the rate of MyfA among 1- and 5-year-olds. Taking into consideration past studies, PCV7 may play a role in preventing the aggravation of AOM in 1-year-olds. When evaluating the effectiveness of PCVs, measures to evaluate severity may be as important as evaluating disease prevention.

Estimación de la Relación Costo-Efectividad de las Vacunas Neumocócicas Conjugadas Prevenar-13 y Synflorix®, Utilizadas en Los Programas de Vacunación de Población Infantil Mexicana.

OBJECTIVE: To estimate the cost effectiveness associated with the use of pneumococcal conjugated vaccines, Prevenar-13 and Synflorix®, in the Mexican pediatric population. METHODS: The cost-effectiveness ratio of instrumenting vaccination programs based upon the use of Prevenar-13 and Synflorix® in the Mexican pediatric population was estimated by using a Markov's simulation model. The robustness of the conclusions reached on cost-effectiveness for both vaccines was assayed through an univariate and probabilistic sensitivity analysis that included all of the parameters considered by the model. RESULTS: Synflorix® was dominant over Prevenar-13 in the cost-utility analysis; the former generated more quality-adjusted life years at a lower cost and with a lower incremental cost-utility ratio. Based on the cost-effective analysis, Prevenar-13 generated more life years gained but at a higher cost. The use of Prevenar-13 originated a higher incremental cost-effectiveness ratio and, therefore, it was not cost-effective as compared with Synflorix®. CONCLUSIONS: Even though the simulations for Prevenar-13 and Synflorix® revealed both of them to be cost-effective when used to instrument pediatric vaccination campaigns in Mexico, Synflorix® had a better cost-utility/effectiveness profile. In addition, although Prevenar-13 and Synflorix® produced equivalent health outcomes, the overall analysis predicted that Synflorix® would save 360 million Mexican pesos, as compared with Prevenar-13.

A systematic review of the burden of vaccine preventable pneumococcal disease in UK adults.

BACKGROUND: Invasive pneumococcal disease (IPD) and pneumococcal pneumonia are common and carry a significant morbidity and mortality. Current strategies to prevent pneumococcal disease are under review in the United Kingdom (UK). We conducted a systematic review to evaluate the burden of vaccine type adult pneumococcal disease specifically in the UK. METHODS: A systematic review conducted and reported according to MOOSE guidelines. Relevant studies from 1990 to 2015 were included. The primary outcome was the incidence of vaccine type pneumococcal disease, focussing on the pneumococcal polysaccharide vaccine (PPSV), the 13-valent conjugate vaccine (PCV13) and the 7-valent conjugate vaccine (PCV7). RESULTS: Data from surveillance in England and Wales from 2013/14 shows an incidence of 6.85 per 100,000 population across all adult age groups for IPD, and an incidence of 20.58 per 100,000 population in those aged >65 years. The corresponding incidences for PCV13 serotype IPD were 1.4 per 100,000 and 3.72 per 100,000. The most recent available data for community-acquired pneumonia (CAP) including non-invasive disease showed an incidence of 20.6 per 100,000 for adult pneumococcal CAP and 8.6 per 100,000 population for PCV13 serotype CAP. Both IPD and CAP data sources in the UK suggest an ongoing herd protection effect from childhood PCV13 vaccination causing a reduction in the proportion of cases caused by PCV13 serotypes in adults. Despite this, applying the incidence rates to UK population estimates suggests more than 4000 patients annually will be hospitalised with PCV13 serotype CAP and more than 900 will be affected by IPD, although with a trend for these numbers to decrease over time. There was limited recent data on serotype distribution in high risk groups such as those with chronic respiratory or cardiac disease and no data available for vaccine type (VT) CAP managed in the community where there is likely to be a considerable unmeasured burden. CONCLUSION: The most recent available data suggests that VT pneumococcal disease continues to have a high burden in UK adults despite the impact of childhood PCV13 vaccination. IPD estimates represent only a fraction of the total burden of pneumococcal disease. STUDY REGISTRATION: PROSPERO CRD42015025043.

The health and economic impact of vaccination with 7-valent pneumococcal vaccine (PCV7) during an annual influenza epidemic and influenza pandemic in China.

BACKGROUND: China has experienced several severe outbreaks of influenza over the past century: 1918, 1957, 1968, and 2009. Influenza itself can be deadly; however, the increase in mortality during an influenza outbreak is also attributable to secondary bacterial infections, specifically pneumococcal disease. Given the history of pandemic outbreaks and the associated morbidity and mortality, we investigated the cost-effectiveness of a PCV7 vaccination program in China from the context of typical and pandemic influenza seasons. METHODS: A decision-analytic model was employed to evaluate the impact of a 7-valent pneumococcal vaccine (PCV7) infant vaccination program on the incidence, mortality, and cost associated with pneumococcal disease during a typical influenza season (15% flu incidence) and influenza pandemic (30% flu incidence) in China. The model incorporated Chinese data where available and included both direct and indirect (herd) effects on the unvaccinated population, assuming a point in time following the initial introduction of the vaccine where the impact of the indirect effects has reached a steady state, approximately seven years following the implementation of the vaccine program. Pneumococcal disease incidence, mortality, and costs were evaluated over a one year time horizon. Healthcare costs were calculated using a payer perspective and included vaccination program costs and direct medical expenditures from pneumococcal disease. RESULTS: The model predicted that routine PCV7 vaccination of infants in China would prevent 5,053,453 cases of pneumococcal disease and 76,714 deaths in a single year during a normal influenza season.The estimated incremental-cost-effectiveness ratios were ¥12,281 (US$1,900) per life-year saved and ¥13,737 (US$2,125) per quality-adjusted-life-year gained. During an influenza pandemic, the model estimated that routine vaccination with PCV7 would prevent 8,469,506 cases of pneumococcal disease and 707,526 deaths, and would be cost-saving. CONCLUSIONS: Routine vaccination with PCV7 in China would be a cost-effective strategy at limiting the negative impact of influenza during a typical influenza season. During an influenza pandemic, the benefit of PCV7 in preventing excess pneumococcal morbidity and mortality renders a PCV7 vaccination program cost-saving.

Revision sistematica de intercambiabilidad de las vacunas conjugadas contra neumococo / Systematic review of the interchangeability of conjugate vaccines against pneumococcus

ANTECEDENTES: Las vacunas conjugadas han demostrado ser efectivas en reducir la incidencia de enfermedad invasiva ocasionada por Streptococo Pneumoniae. La primera vacuna de este tipo en ser aprobada para su uso consto de 7 serotipos. Actualmente se encuentran disponibles otros dos tipos de vacunas una de 10 serotipos, y otra de 13 serotipos. Diversos países han introducido estas nuevas vacunas en sus programas con el fin de mejorar la protección a serotipos de neumococo no incorporados previamente. Esto ha conllevado a cohortes de infantes en los que se ha debido dar un intercambio del tipo de vacuna con el que se empezó el esquema de inmunización. OBJETIVO: Iidentificar la evidencia disponible en cuanto al intercambio entre VNC7, VNC10 o VNC13 en cualquiera de las dosis del esquema de vacunación en niños menores de dos años. MÉTODOS: Se realizó una búsqueda con términos pre-especificados en las bases de datos incluidos en Ovid/Medline, Embase y Cochrane Central Register of Controlled Trials; en el periodo de Enero de 1995 a Agosto del 2013, no se incluyeron presentaciones a congresos o reuniones científicas. Se incluyeron estudios experimentales aleatorizados, cuasi experimentales o de cohortes que evalúen la respuesta inmunológica posterior al intercambio del tipo de vacuna conjugada con que se inició el esquema de vacunación. Se excluyeron estudios que se evalúen el uso de vacunas de 9 u 11 serotipos. La respuesta inmune se evaluó a través de la concentración media geométrica de inmunoglobulina G (IgG) específica para cada serotipo, así como en base a la proporción de sujetos con niveles ≥0.35 µ/mL o su equivalente. La actividad funcional antibacteriana se evaluó mediante la prueba de opsonofagocitacion (PO) en base a sus títulos medios geométricos (TMG) para cada serotipo o la proporción de sujetos con títulos ≥1:8. RESULTADOS: Se identificaron 2004 citas en la búsqueda en las bases de datos electrónicas y mediante referencias secundarias, se identificaron un total de 7 estudios para revisión a texto completo, de los cuales finalmente cuatro estudios para ser incluidos en la revisión. Intercambio de la dosis de refuerzo, esquema 3+1: Se identificaron dos estudios, que evaluaron el cambio en la dosis de refuerzo de VNC7 a VNC10 o VNC13 respectivamente. Comparado con el grupo que permaneció en VNC7 los que cambiaron de tipo de vacuna mostraron CMG menores para los serotipos 6B, 14 y 23F en el caso de VNC10; así como para el serotipo 9V y 14 con VNC13. Sin embargo >90% de sujetos lograron cifras ≥0.35 µ/mL de CMG de IgG sero- especifico o su equivalente. Intercambio de las dosis infantiles, esquema 2+1: Se identificó un solo estudio que evaluó el cambio de VNC7 a VNC13, el cual consto de dos grupos, el primero recibió VNC13 en la segunda dosis infantil y el segundo grupo solo recibió VNC13 en el refuerzo. Tras la segunda dosis infantil se observaron niveles menores en relación a los otros serotipos en el mismo grupo para el serotipo 6B y 23F los cuales mostraron un incremento marcado tras la dosis de refuerzo. Aunque los resultados fueron consistentes con lo observado previamente para este tipo de esquema, el estudio no incluyo un grupo control ni reporto proporción de sujetos con niveles ≥0.35 µ/mL de IgG seroespecifico. Intercambio de dosis refuerzo más dosis adicional de captura, esquema 3+1+1: Se encontró un estudio que evaluó en sujetos que iniciaron el esquema de vacunación con VNC7, e uso de VNC13 en el refuerzo y la adición de una dosis de captura. Los resultados se reportaron posteriores a la segunda dosis de VNC13, se observó que tras la dosis de captura todos los serotipos comunes y no comunes alcanzaron un porcentaje de sujetos con CMG de IgG ≥0.35 µ/mL superior al 95%. CONCLUCIONES: Se cuenta con información de intercambio de vacunas neumocicas conjugadas para un esquema similar al peruano solo para el cambio de VNC7 a VNC13, con desenlaces inmunológicos similares a lo observado para este tipo de esquema cuando no se da intercambio del tipo de vacuna con el que inicio. En tanto no se encontraron estudios que evalúen el intercambio entre VNC10 y VNC13, recomendamos para este caso de forma análoga a lo estipulado por el comité técnico de la Organización Mundial de Salud: que el esquema de vacunación debe completarse con el tipo de vacuna neumococica conjugada con el que se inició; de no ser esto factible y en vista que retrasar el calendario de inmunización conlleva un riesgo mayor, puede considerarse el intercambio de vacunas.(AU)