Prescribing antibiotics for children with dengue infection in Taiwan: who are at risk and who are high prescribers?

Inappropriate antibiotic use contributes to antimicrobial resistance, a global public health threat. The non-specific manifestations of dengue, itself a growing public health threat, lead to avoidable empiric antibiotic prescription, particularly in children. In this national pooled population-based cross-sectional study, we evaluated child and physician characteristics associated with antibiotics prescription in confirmed dengue cases in Taiwan. Linking national health care insurance claims and reports of confirmed dengue cases from 2008 to 2015, there were 7086 children with confirmed dengue with 21 744 outpatient visits and 2520 inpatient admissions. We assessed the presence of antibiotic prescription in outpatient and inpatient settings separately a week before or after the confirmation date. Logistic regression models with generalized estimating equations were applied to identify patient, practitioner, and other factors associated with antibiotic prescription. A total of 29.4% of children <18 years old with dengue who did not have a concomitant bacterial infection were prescribed antibiotics during the 14-day assessment period. Antibiotics prescription was reduced from 13.5% to 6.3% and from 43.2% to 19.3% in outpatient and inpatient settings, respectively, after dengue was confirmed. Young children were more likely to receive antibiotics. Significant variations in antibiotic prescribing across physicians were observed only in outpatient settings: physicians ≥60 years old and physicians practicing at clinics and in non-urban facilities were more likely to prescribe antibiotics. Antibiotics were less likely to be prescribed during an exceptional 2-year epidemic than in other years. Antibiotic prescribing for dengue, an arboviral infection affecting half of the global population, was shown to occur in 29% of paediatric cases in Taiwan. That potentially avoidable antibiotic consumption could be reduced by improving antibiotic stewardship, informed by understanding the conditions under which antibiotics are prescribed and the availability of prevention strategies for viral diseases, including dengue. We identified a number of such factors in this national population-based study.

Fabrication of nanocrystal forms of á´ -cycloserine and their application for transdermal and enteric drug delivery systems.

ᴅ-cycloserine (DCS), an FDA-approved medicine for the treatment of tuberculosis, is also a partial agonist at the glycine recognition site of N-methyl-ᴅ-aspartate (NMDA) receptor and has shown significant treatment efficacy for central nervous system (CNS) disorders including depression, schizophrenia, Alzheimer's disease, and post-traumatic stress disorder. The physicochemical properties of DCS, however, limit the options of formulation and medicinal applications of DCS, and warrants further investigation for the development of CNS therapeutics. Nanocrystals play an important role in pharmaceutic design and development. The properties of nanocrystals are remarkably different from their bulk material counterpart, attributed to the large surface-area-to-volume ratio which can improve the bioavailability. In this study, for the first time, DCS, a highly water-soluble compound, has formed nanocrystals and this was confirmed by scanning electronic microscopy and X-ray powder diffraction. Furthermore, DCS nanocrystals were applied to several formulations to test their stability and then to the in vitro Franz diffusion test with reservoir patch formulation as well as in vivo pharmacokinetics study with enteric capsules. We tested these formulations regarding their nanocrystal physical properties, size effect, and dissolution rate, respectively. We found that DCS nanocrystals showed good performance in the Franz diffusion test and rodent pharmacokinetic studies due to the nanoparticle size and faster dissolution as compared with the commercial DCS powder. These DCS nanocrystal formulations could offer a new approach for the development of an advanced drug delivery system for the treatment of CNS disorders.

Advanced Age and Increased Risk for Severe Outcomes of Dengue Infection, Taiwan, 2014-2015.

Dengue, a mosquitoborne flavivirus infection, is increasingly a disease of older adults who are more likely to have chronic diseases that confer risk for severe outcomes of dengue infection. In a population-based study in Taiwan, adjusted risks for dengue-related hospitalization, intensive care unit admission, and death increased progressively with age.

Population-based assessment of factors influencing antibiotic prescribing for adults with dengue infection in Taiwan.

BACKGROUND: Antibiotic treatment for dengue is likely considerable and potentially avoidable but has not been well characterized. This study aimed to assess antibiotic prescribing for confirmed dengue cases in outpatient and inpatient settings and to identify associated patient, physician and contextual factors. METHODS: 57,301 adult dengue cases reported in Taiwan between 2008-2015 were analyzed. We assessed both outpatient and inpatient claims data of dengue patients from a week before to a week after their dengue infections were confirmed under Taiwan's National Health Insurance program. A multivariable logistic regression with generalized estimating equations was used to estimate the probability of antibiotic prescribing in dengue patients. RESULTS: Overall, 24.6% of dengue patients were prescribed an antibiotic during the 14 day-assessment period. Antibiotics were prescribed in 6.1% and 30.1% of outpatient visits and inpatient admissions, respectively. Antibiotic prescriptions were reduced by ~50% in epidemic years. Among inpatients, advanced age, females, and major comorbidities were risk factors for receipt of an antibiotic; antibiotics were used in 26.0% of inpatients after dengue was diagnosed. Significant differences in antibiotic prescribing practices were observed among physicians in outpatient settings but not in inpatient settings. CONCLUSIONS: In addition to patient and physician demographic characteristics, contextual factors such as care setting and during epidemics significantly influenced prescription of antibiotics. Characterization of prescribing patterns should help direct programs to curb antibiotic prescribing.

The importance of influenza vaccination during the COVID-19 pandemic.

The COVID-19 pandemic and the measures taken to mitigate its spread have had a dramatic effect on the circulation patterns of other respiratory viruses, most especially influenza viruses. Since April 2020, the global circulation of influenza has been markedly reduced; however, it is still present in a number of different countries and could pose a renewed threat in the upcoming Northern Hemisphere winter. Influenza vaccination remains the most effective preventive measure that we have at our disposal against influenza infections and should not be ignored for the 2021-2022 season.

A Population-Based Cohort Study on Chronic Comorbidity Risk Factors for Adverse Dengue Outcomes.

The global burden of dengue is increasing against a background of rising global prevalence of chronic noncommunicable diseases (NCDs) and an epidemiological shift of dengue toward older age groups. The contribution of NCDs toward risk for adverse clinical and healthcare utilization outcomes was assessed in a national linked-database study. About 51,433 adult dengue cases between 2014 and 2015 were assessed for outpatient and inpatient claims data in Taiwan's National Health Insurance Research Database for the 30 days after their dengue diagnosis. A multivariable logistic regression with generalized estimating equations was used to estimate the probability of adverse dengue outcomes in patients with NCDs compared with dengue patients without underlying diseases. Rheumatoid arthritis and related disease were associated with the highest risk of hospitalization after dengue diagnosis (odds ratio: 1.78; 95% CI: 1.37-2.30), followed by stroke, chronic kidney disease (CKD), liver cirrhosis, asthma, coronary artery disease, chronic obstructive pulmonary disease, diabetes, congestive heart failure, hypertension, and malignancy. Chronic kidney disease and diabetes were associated with higher risks of hospitalization, intensive care unit (ICU) use, and all-cause mortality. After adjusting for socioeconomic status and other variables, the number of coexisting chronic diseases was associated with increasing risk of adverse dengue outcomes. Specific NCDs were associated with longer hospitalizations, ICU admission, and higher healthcare costs. Quantifying the risks of adverse dengue outcomes and health expenditures among dengue patients with preexisting NCDs provides insights for improved clinical management and essential inputs for health economic analyses on the cost-benefit of risk-based routine or catch-up immunization programs.

Assessment of the benefits of seasonal influenza vaccination: Elements of a framework to interpret estimates of vaccine effectiveness and support robust decision-making and communication.

Systematic reviews and meta-analyses confirm that influenza vaccination reduces the risk of influenza illness by between about 40% and 60% in seasons when circulating influenza stains are well matched to vaccine strains. Influenza vaccine effectiveness (IVE) estimates, however, are often discordant and a source of confusion for decision makers. IVE assessments are increasingly publicized and are often used by policy makers to make decisions about the value of seasonal influenza vaccination. But there is limited guidance on how IVE should be interpreted or used to inform policy. There are several limitations to the use of IVE for decision-making: (a) IVE studies have methodological issues that often complicate the interpretation of their value; and (b) the full impact of vaccination will almost always be greater than the impact assessed by a point estimate of IVE in specific populations or settings. Understanding the strengths and weaknesses of study methodologies and the fundamental limitations of IVE estimates is important for the accuracy of interpretations and support of policy makers' decisions. Here, we review a comprehensive set of issues that need to be considered when interpreting IVE and determining the full benefits of influenza vaccination. We propose that published IVE values should be assessed using an evaluative framework that includes influenza-specific outcomes, types of VE study design, and confounders, among other factors. Better interpretation of IVE will improve the broader assessment of the value of influenza vaccination and ultimately optimize the public health benefits in seasonal influenza vaccination.

Cell culture-derived influenza vaccines in the severe 2017-2018 epidemic season: a step towards improved influenza vaccine effectiveness.

The 2017-2018 seasonal influenza epidemics were severe in the US and Australia where the A(H3N2) subtype viruses predominated. Although circulating A(H3N2) viruses did not differ antigenically from that recommended by the WHO for vaccine production, overall interim vaccine effectiveness estimates were below historic averages (33%) for A(H3N2) viruses. The majority (US) or all (Australian) vaccine doses contained multiple amino-acid changes in the hemagglutinin protein, resulting from the necessary adaptation of the virus to embryonated hen's eggs used for most vaccine manufacturing. Previous reports have suggested a potential negative impact of egg-driven substitutions on vaccine performance. With BARDA support, two vaccines licensed in the US are produced in cell culture: recombinant influenza vaccine (RIV, Flublok™) manufactured in insect cells and inactivated mammalian cell-grown vaccine (ccIIV, Flucelvax™). Quadrivalent ccIIV (ccIIV4) vaccine for the 2017-2018 influenza season was produced using an A(H3N2) seed virus propagated exclusively in cell culture and therefore lacking egg adaptative changes. Sufficient ccIIV doses were distributed (but not RIV doses) to enable preliminary estimates of its higher effectiveness relative to the traditional egg-based vaccines, with study details pending. The increased availability of comparative product-specific vaccine effectiveness estimates for cell-based and egg-based vaccines may provide critical clues to inform vaccine product improvements moving forward.

Influenza vaccination in children primed with MF59-adjuvanted or non-adjuvanted seasonal influenza vaccine.

Routine annual influenza immunization is increasingly recommended in young children. We compared the safety and immunogenicity of vaccination with trivalent inactivated influenza vaccine (TIV) versus MF59-adjuvanted TIV (aTIV) in children who received 2 half or full doses of aTIV or TIV, or non-influenza control vaccine, in an efficacy trial conducted 2 years earlier. 197 healthy children aged 30-96 months were randomized to receive vaccination with aTIV or TIV in 2010. To evaluate responses to the first follow-up seasonal vaccination after priming we excluded children who received influenza vaccine(s) in the 2009 pandemic year leaving 40 children vaccinated with aTIV, 26 children with TIV and 10 children with aTIV after a control vaccine in the parent study. Hemagglutination inhibiting antibodies were assayed on Days 1, 22 and 181. aTIV vaccination produced 6.9 to 8.0-fold higher antibody responses than the reference TIV-TIV regimen against A/H3N2 and B strains, which remained higher 6 months following vaccination. The response to the B/Victoria lineage antigen in the second year's vaccine (the first vaccine contained a B/Yamagata lineage antigen) demonstrated that aTIV primed for an adequate response after a single dose on Day 22 (GMTs 160, 95 to antigens in the 2 lineages, respectively), whereas TIV did not (GMTs 38, 20). Vaccination with aTIV produced slightly higher but acceptable local and systemic reactogenicity compared to TIV-TIV and TIV-aTIV mixed regimens. Within the limitations of a small study, the strong immune responses support the use of aTIV for vaccination in young children.

Performance characteristics of qualified cell lines for isolation and propagation of influenza viruses for vaccine manufacturing.

Cell culture is now available as a method for the production of influenza vaccines in addition to eggs. In accordance with currently accepted practice, viruses recommended as candidates for vaccine manufacture are isolated and propagated exclusively in hens' eggs prior to distribution to manufacturers. Candidate vaccine viruses isolated in cell culture are not available to support vaccine manufacturing in mammalian cell bioreactors so egg-derived viruses have to be used. Recently influenza A (H3N2) viruses have been difficult to isolate directly in eggs. As mitigation against this difficulty, and the possibility of no suitable egg-isolated candidate viruses being available, it is proposed to consider using mammalian cell lines for primary isolation of influenza viruses as candidates for vaccine production in egg and cell platforms. To investigate this possibility, we tested the antigenic stability of viruses isolated and propagated in cell lines qualified for influenza vaccine manufacture and subsequently investigated antigen yields of such viruses in these cell lines at pilot-scale. Twenty influenza A and B-positive, original clinical specimens were inoculated in three MDCK cell lines. The antigenicity of recovered viruses was tested by hemagglutination inhibition using ferret sera against contemporary vaccine viruses and the amino acid sequences of the hemagglutinin and neuraminidase were determined. MDCK cell lines proved to be highly sensitive for virus isolation. Compared to the virus sequenced from the original specimen, viruses passaged three times in the MDCK lines showed up to 2 amino acid changes in the hemagglutinin. Antigenic stability was also established by hemagglutination inhibition titers comparable to those of the corresponding reference virus. Viruses isolated in any of the three MDCK lines grew reasonably well but variably in three MDCK cells and in VERO cells at pilot-scale. These results indicate that influenza viruses isolated in vaccine certified cell lines may well qualify for use in vaccine production.

Fluad®-MF59®-Adjuvanted Influenza Vaccine in Older Adults.

Influenza directly or indirectly contributes to the four leading causes of global mortality, at rates that are highest in older adults. As the proportion of older adults in the Korean population is greater than in most other countries, influenza prevention is a greater public health priority in Korea than elsewhere. Conventional inactivated influenza vaccine (IIV) is less immunogenic and efficacious (-50%) in older than in young adults, but adjuvanting the vaccine with oil-in-water emulsion MF59® increases immunogenicity, resulting in comparatively higher levels of hemagglutination inhibition antibodies and greater protection against all influenza, as well as cases requiring hospitalization. A recent observational study demonstrated that the adjuvanted vaccine protected older adults against influenza in a year when nonadjuvanted IIV was ineffective. In another multiyear study, the adjuvanted vaccine was estimated to be 25% more effective in preventing pneumonia and influenza hospitalizations compared to nonadjuvanted vaccine. Although MF59-adjuvanted vaccine is transiently more reactogenic than nonadjuvanted vaccine, there is no evidence that it increases risks for serious adverse events, including those with an autoimmune etiology. Experience thus far indicates a favorable balance of benefit to risk for MF59. This may reflect the adjuvant's mechanism of action in which the squalene oil emulsion increases antibody responses to co-administered antigen without acting more generally as an immunopotentiator.

Altered response to A(H1N1)pnd09 vaccination in pregnant women: a single blinded randomized controlled trial.

BACKGROUND: Pregnant women were suspected to be at particular risk when H1N1pnd09 influenza became pandemic in 2009. Our primary objective was to compare the immune responses conferred by MF59®-adjuvanted vaccine (Focetria®) in H1N1pnd09-naïve pregnant and non-pregnant women. The secondary aims were to compare influences of dose and adjuvant on the immune response. METHODS: The study was nested in the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2010) pregnancy cohort in 2009-2010 and conducted as a single-blinded block-randomised [1∶1∶1] controlled clinical trial in pregnant women after gestational week 20: (1) 7.5 µg H1N1pnd09 antigen with MF59-adjuvant (Pa7.5 µg); (2) 3.75 µg antigen half MF59-adjuvanted (Pa3.75 µg); (3) 15 µg antigen unadjuvanted (P15 µg); and in non-pregnant women receiving (4) 7.5 µg antigen full adjuvanted (NPa7.5 µg). Blood samples were collected at baseline, 3 weeks, 3 and 10 months after vaccination, adverse events were recorded prospectively. RESULTS: 58 pregnant women were allocated to Pa7.5 µg and 149 non-pregnant women were recruited to NPa7.5 µg. The sero-conversion rate was significantly increased in non-pregnant (NPa7.5 µg) compared with pregnant (Pa7.5 µg) women (OR = 2.48 [1.03-5.95], p = 0.04) and geometric mean titers trended towards being higher, but this difference was not statistically significant (ratio 1.27 [0.85-1.93], p = 0.23). The significant titer increase rate showed no difference between pregnant (Pa7.5 µg) and non-pregnant (NPa7.5 µg) groups (OR = 0.49 [0.13-1.85], p = 0.29). CONCLUSION: Our study suggests the immune response to the 7.5 µg MF59-adjuvanted Focetria® H1N1pnd09 vaccine in pregnant women may be diminished compared with non-pregnant women. TRIAL REGISTRATION: ClinicalTrials.gov NCT01012557.

In vitro assessment of the allergenicity of novel MF59-adjuvanted pandemic H1N1 influenza vaccine produced in dog kidney cells.

A licensed inactivated MF59-adjuvanted seasonal influenza vaccine (Optaflu) produced in canine kidney cells (MDCK 33016-PF) contained no egg proteins and did not trigger degranulation in rat basophilic leukemia (RBL) cells passively sensitized with human anti-dog IgE, supporting its safe use in dog-allergic individuals. The cell-derived pandemic H1N1 influenza vaccine was also adjuvanted with the emulsion adjuvant MF59, and support for its similar safe use was sought. We sought to evaluate in vitro allergenicity of the MF59-adjuvanted cell-derived pandemic H1N1 influenza vaccine in subjects with dog allergy, with a mediator release assay. RBL-2H3 cells transfected with human Fcε receptor type 1 were sensitized with sera from adult dog-allergic subjects and stimulated with serial dilutions of pandemic H1N1 influenza vaccine and dog dander extract. ß-N-hexosaminidase release (NHR) was used as a marker of RBL degranulation.. Median dog dander-specific IgE in 30 dog-allergic subjects was 27.7 kU(A)/L (range 10.1; > 100); and in 5 dog non-allergic subjects was < 0.35 kU(A)/L (UniCAP system). Median (range) maximum NHR in dog-allergic subjects was: pandemic H1N1 influenza vaccine 1.1% (0; 4.4) and dog dander 6.9% (0.7; 37.3), P < 0.001. In conclusion, MF59-adjuvanted pandemic H1N1 influenza vaccine produced in continuous canine kidney cells did not trigger degranulation in RBL cells passively sensitized with human anti-dog IgE, supporting its safe use in dog-allergic individuals.

New technologies for influenza vaccines.

Influenza vaccine preparations have been administered to humans since the late 1930s, and the diversity of approaches in licensed trivalent seasonal or monovalent pandemic products is unparalleled by vaccines against any other target. These approaches include inactivated whole virus vaccines, detergent or solvent "split" vaccines, subunit vaccines, live attenuated vaccines, adjuvanted vaccines, intramuscular vaccines, intradermal vaccines, intranasal vaccines, egg-produced vaccines and mammalian cell culture-produced vaccines. The challenges of influenza immunization, including multiple co-circulating strains, antigenic change over time, a broad age spectrum of disease, and the threat of pandemics, continue to drive the development of new approaches. This review describes some of the new approaches to influenza immunization that are the subjects of active research and development.

MF59 adjuvanted seasonal and pandemic influenza vaccines.

MF59-adjuvanted seasonal trivalent inactivated (ATIV) vaccine licensed since 1997 and MF59-adjuvanted pandemic H1N1 vaccines have been distributed to approximately 80M persons. Addition of the emulsion adjuvant to inactivated vaccine formulations provides for higher levels of antibody to the viral hemagglutinin (HA) in less responsive older adults, infants and children which, in the case of the pandemic vaccine, allowed only 3.75 µg of the HA to be immunogenic. The adjuvant also stimulates production of more broadly-reactive antibodies against strains that are mismatched to those in the vaccine, a potential advantage in the face of perennial influenza virus antigenic drift. In a field trial, ATIV was 89% efficacious in preventing laboratory-confirmed influenza in 6-<72 month old children, 81% more efficacious than the unadjuvanted control split vaccine while, in older adults, ATIV reduced community-acquired pneumonia and influenza hospitalizations in adults >65 years old by 23% compared to unadjuvanted vaccine, in an observational study. The effectiveness of MF59 adjuvanted split pandemic H1N1 vaccine was 74% overall. Unadjuvanted pandemic vaccine was poorly immunogenic in HIV-infected persons, whereas their responses to MF59-adjuvanted vaccine were similar to those of healthy controls. Analyses of the clinical trials and pharmacovigilance databases and observational studies have shown that while MF59-adjuvanted influenza vaccines are more locally reactogenic, they have not been associated with an increased risk for various adverse effects (AE) of special interest, including unsolicited neurological or autoimmune events.

Estimated global incidence of Japanese encephalitis: a systematic review.

OBJECTIVE: To update the estimated global incidence of Japanese encephalitis (JE) using recent data for the purpose of guiding prevention and control efforts. METHODS: Thirty-two areas endemic for JE in 24 Asian and Western Pacific countries were sorted into 10 incidence groups on the basis of published data and expert opinion. Population-based surveillance studies using laboratory-confirmed cases were sought for each incidence group by a computerized search of the scientific literature. When no eligible studies existed for a particular incidence group, incidence data were extrapolated from related groups. FINDINGS: A total of 12 eligible studies representing 7 of 10 incidence groups in 24 JE-endemic countries were identified. Approximately 67,900 JE cases typically occur annually (overall incidence: 1.8 per 100,000), of which only about 10% are reported to the World Health Organization. Approximately 33,900 (50%) of these cases occur in China (excluding Taiwan) and approximately 51,000 (75%) occur in children aged 0-14 years (incidence: 5.4 per 100,000). Approximately 55,000 (81%) cases occur in areas with well established or developing JE vaccination programmes, while approximately 12,900 (19%) occur in areas with minimal or no JE vaccination programmes. CONCLUSION: Recent data allowed us to refine the estimate of the global incidence of JE, which remains substantial despite improvements in vaccination coverage. More and better incidence studies in selected countries, particularly China and India, are needed to further refine these estimates.