Daniela de Florentiis

High-dose daptomycin in documented Staphylococcus aureus infections

Daptomycin is approved at a dose of 4-6 mg/kg/day for the treatment of complicated skin and soft-tissue infection and Staphylococcus aureus bloodstream infection. Clinical experience with doses >6 mg/kg/day is limited, but data reported to date suggest that daptomycin can be safe and effective at higher doses. We describe our experience with daptomycin at doses >6 mg/kg/day and ≤6 mg/kg/day for S. aureus infections. A retrospective chart review of all patients treated with daptomycin from January 2008 to 28 February 2010 was performed. During the study period, 53 patients received daptomycin, including 22 patients receiving daptomycin at a standard dose (SD) (mean 5 mg/kg/day, range 4-6 mg/kg/day) and 31 patients receiving a higher dose (HD) (mean 8 mg/kg/day, range 7-9 mg/kg). The median treatment duration was 13.5 days and 19 days for the SD and HD groups, respectively. Clinical success was observed in 16/22 patients (73%) in the SD group and 29/31 patients (94%) in the HD group (P=0.05). Microbiological success was observed in 13/19 patients (68%) and 27/29 patients (93%) in the SD and HD groups, respectively (P<0.05). Of the 53 patients, 2/22 treated with SD daptomycin and 3/31 treated with HD daptomycin experienced a grade 1 adverse event while receiving therapy (i.e. anaemia, diarrhoea, nausea, hypokalaemia and arthralgia) but did not require discontinuation of daptomycin treatment. These results suggest that daptomycin may be used at doses higher than 6 mg/kg/day without toxicity and possibly with better outcome than conventional doses. We recommend further randomised controlled prospective studies with higher doses of daptomycin.

Inactivated influenza vaccines: recent progress and implications for the elderly.

The current public health strategy for the containment of influenza is annual vaccination, which is recommended for the elderly and for those in risk factor categories that present the highest morbidity and mortality. However, because the immune response in the elderly is known to be less vigorous than in younger adults, research in the last decade has focused on improving the immune response to vaccination and increasing the protection of aged populations.The decreased efficacy of vaccines in the elderly is due to several factors, such as a decrease in the number of Langerhans cells, the limited capacity of dendritic cells to present antigen, defects in the expression of Toll-like receptors and the reduced expression of MHC class I and II molecules. Also, production of mature naive T cells by the thymus decreases with age.Among several approaches proposed to address the need for more immunogenic vaccines compared with conventional agents, the most well proven is the use of adjuvants.The first licensed adjuvant, aluminium-based mineral salts (alum), introduced in the 1920s, remains the standard worldwide adjuvant for human use and it has been widely used for almost a century. However, the addition of alum adjuvant to a split or subunit influenza vaccine has induced only marginal improvements. Other adjuvants have been developed and approved for human use since 1997; in particular, MF59, an oil-in-water adjuvant emulsion of squalene, which is able to increase immunogenicity of seasonal, prepandemic and pandemic subunit vaccines while maintaining acceptable safety and tolerability profiles. More recently, another oil-in-water emulsion, AS03, has been approved as a component of pre-pandemic H5N1 and pandemic H1N1 2009 vaccines.Besides adjuvants, several other strategies have been assessed to enhance antibody response in the elderly and other less responsive subjects, such as high-dose antigen vaccines, carrier systems (liposomes/virosomes) and the intradermal route of immunization. In particular, the potential of intradermal vaccination is well documented and the recent availability of an appropriate injection system, which combines simplicity, safety and ease of use, has allowed evaluation of the tolerability, safety and immunogenicity of the intradermal influenza vaccine in large numbers of subjects. Data that emerged from large clinical trials showed an improved immunogenicity compared with that of standard vaccine.Observational studies or comparisons between adjuvanted, intradermal or high-dose versus conventional vaccines are needed to evaluate whether the greater immunogenicity observed in a number of recent studies is correlated with greater protection against influenza and influenza-related complications and death.

Fluzone ® Intradermal vaccine: a promising new chance to increase the acceptability of influenza vaccination in adults

On May 9 2011, the US FDA approved Sanofi Pasteur’s Fluzone® Intradermal influenza vaccine, the first influenza vaccine licensed in the USA that uses a new microinjection system for intradermal delivery of vaccines (Soluvia™, Becton Dickinson). Its antigen content is lower (9 µg hemagglutinin per strain) than the conventional intramuscular vaccine (15 µg) and it is indicated for active immunization of adults aged between 18 and 64 years. Data from the clinical trial assessing immunogenicity and safety of Fluzone Intradermal in adults were consistent with substantial experience accumulated with Intanza® 9 µg, the intradermal vaccine licensed on February 26 2009 and launched during the 2010/2011 season in Europe. Fluzone Intradermal is safe and its immunogenicity comparable with that of conventional intramuscular vaccines. Obtaining optimal acceptability of intradermal vaccines may represent an additional asset to help increase the coverage of influenza vaccination in young adults.

Intanza® 15 mcg intradermal influenza vaccine elicits cross-reactive antibody responses against heterologous A(H3N2) influenza viruses

The aim of the present study was to explore the ability of Intanza(®) 15 μg, the intradermal (ID) trivalent inactivated split-virion influenza vaccine containing 15 μg hemagglutinin per strain, to enhance the antibody responses against heterologous circulating H3N2 strains in adults 60 years and older. During the 2006-2007 influenza season, subjects aged 60 years or older were randomly assigned to receive one dose of ID or an intramuscular (IM, Vaxigrip(®)) influenza vaccine, which contained the reassortant A/Wisconsin/67/05(H3N2) strain as the H3N2 component. Antibody responses were assessed against the homologous vaccine strain, against the A/Brisbane/10/07(H3N2) reassortant strain and against four heterologous H3N2 field isolates (A/Genoa/62/05(H3N2), A/Genoa/3/07(H3N2), A/Genoa/2/07(H3N2), A/Genoa/3/06(H3N2)). The viruses tested belonged to three different clades that were closely related antigenically to A/California/7/04(H3N2), A/Nepal/921/06(H3N2) and A/Brisbane/10/07(H3N2). Antibody responses to these viruses were measured in 25 subjects per group using both haemagglutination inhibition (HI) and neutralization (NT) assays. At least one Committee for Medicinal Products for Human Use (CHMP) immunogenicity criteria for vaccine approval in the elderly was reached by both vaccines against all the viruses used in the study. All three CHMP criteria were reached against A/California/7/04(H3N2)-like, A/Nepal/921/06(H3N2)-like and A/Brisbane/10/07(H3N2)-like viruses by Intanza(®) 15 μg ID vaccine, while IM vaccination did not meet seroprotection criteria against circulating A/Nepal/921/06(H3N2)-like and A/Brisbane/10/07(H3N2)-like viruses or seroconversion criteria against A/Brisbane/10/07(H3N2)-like viruses. Post-vaccination HI titer, seroconversion, and seroprotection rates were higher against all viruses in subjects who received Intanza(®) 15 μg. The superiority of the seroprotection rate against the A/Nepal/921/06(H3N2)-like strain attained statistical significance despite the small sample size. Upon Beyer correction for pre-vaccination status, post-immunization HI titers against A/California/7/04(H3N2)-like and A/Brisbane/10/07(H3N2)-like strains and NT post-immunization titers against A/Wisconsin/67/05(H3N2), A/California/7/04(H3N2)-like, A/Brisbane/10/07(H3N2)-like strains were significantly higher in subjects immunized with Intanza(®) 15 μg than in individuals receiving IM vaccine. This study, although limited in the size of study population, demonstrated the broader immune response elicited by an ID influenza vaccine vs. a standard IM influenza vaccine against heterologous viruses including field isolates.

Increasing Incidence of Streptococcus pneumoniae Serotype 19A and Emergence of Two Vaccine Escape Recombinant ST695 Strains in Liguria, Italy, 7 Years after Implementation of the 7-Valent Conjugated Vaccine

ABSTRACT Two serotype 19A (ST695) Streptococcus pneumoniae vaccine escape recombinant strains attributable to capsular switching events were detected by a laboratory surveillance system that is an integral part of a vaccination program begun in Liguria, Italy, in May 2003, an Italian administrative region with long-lasting high coverage, an unusual occurrence in Europe. To our knowledge, this is the first detection of an occurrence of capsular switching outside the United States.

Head-to-head comparison of an intradermal and a virosome influenza vaccine in patients over the age of 60: Evaluation of immunogenicity, cross-protection, safety and tolerability

In the present study we first compare immunogenicity against vaccine and heterologous circulating A(H1N1)pdm09 strains, tolerability and safety of intradermal Intanza® 15 μg and of virosomal adjuvanted, intramuscularly delivered influenza vaccine, Inflexal® V, in healthy elderly volunteers. Five-hundred participants were enrolled in the study and randomly assigned to the two vaccine groups to receive either one dose of Intanza® 15 μg or Inflexal® V vaccine. All subjects reported solicited local and systemic reactions occurred within 7 d after vaccination and unsolicited adverse events up to 21 d post-immunization and any serious adverse event appeared during the study. A subset of 55 participants was randomly selected for immunogenicity and cross-protection evaluations. Serum samples were collected before and 1 and 3 mo after immunization. Antibody responses were measured using hemagglutination inhibition (HI) against all viruses used in the study and neutralization (NT) assays against A(H1N1)pdm09 strains. At least one of the CHMP criteria for influenza vaccine approval in the elderly was met by virosomal vaccine against all the tested viruses; intradermal vaccine met all criteria against all strains. Several parameters of immune response against strains with a different antigenic pattern from that of vaccine A/California/04/09(H1N1)pdm09 were significantly higher in the intradermal vaccine group compared with the virosomal group. Safety and systemic tolerability of both vaccines were excellent, but injection site reactions occurred significantly more frequently in the intradermal vaccination group. Immunogenicity of Intanza® 15 μg intradermal vaccine tended to be higher than that of Inflexal® V against heterologous strains in healthy elderly.

Cross-protection against drifted influenza viruses: Options offered by adjuvanted and intradermal vaccines

Antigenic drift, the evolutionary mechanism of influenza viruses, results in an increased susceptibility of vaccinated subjects against circulating viruses. New vaccines able to grant a broader and cross-reactive immune response against drifted influenza variants are needed. Several strategies were explored to enhance the immunogenicity of plain vaccines: adjuvants, carriers and intradermal administration of influenza vaccine emerge as a promising options. To evaluate the ability of a MF59™-adjuvanted and intradermal influenza vaccine to elicit an effective antibody response against circulating viruses presenting antigenic patterns different from those of the vaccine strains, we compared antibody responses elicited by “implemented” vaccines and conventional intramuscular trivalent inactivated vaccine against heterologous circulating influenza A viruses. Different studies, simulating different epidemiological pictures produced by the natural antigenic drift of seasonal influenza viruses, highlighted the superior cross-reactivity of the antibodies elicited by MF59™ and intradermal vaccines, compared with subunit or split vaccine against heterologous viruses.

Carriage of Streptoccoccus pneumoniae 7 years after implementation of vaccination program in a population with very high and long-lasting coverage, Italy

To evaluate how the 7-valent pneumococcal vaccine (PCV7) programme and the very high vaccination coverage reached for over 4 years affected the prevalence of Streptoccoccus pneumoniae serotypes in the paediatric population and to evaluate demographic, behavioural and risk factors for carriage in the post-vaccination era, a cross-sectional study on nasopharyngeal carriage was performed. Six hundred sixty-nine children under the age of 5, representative of the open population, were enrolled by cluster sampling. High sensitive techniques for detection of multi-serotype carriage, i.e. broth enrichment and real-time PCR and sequential PCRs for detection and typing, respectively, were used. Of the 669 enrolled children, 97.8% were compliant with the recommended PCV7 vaccination schedule. Post-stratification adjustment for age was applied considering the Ligurian population as standard population. Age-weighted carriage rate was 50.1% and 78% of carriers were colonized by more than one serotype. The prevalence of carriage increased with age from 22% in the first year of life, to 48.6% in the second year of life and to 60% in the 25-59 month age group. Age-weighted prevalence of any of the PCV7, PCV10 or PCV13 serotypes was 10.3%, 20.3% and 27.5%, respectively. PCV7 serotypes were mainly represented by serotype 4 that was carried since the 3rd year of life and was responsible for invasive pneumococcal disease (IPD) and non-IPD in adults, but not in children confirming the high vaccine effectiveness. Among the serotypes included in recently available vaccines, serotypes 5 and 19A showed a higher prevalence, being carried by 15.2% and 8.8% of the population, respectively. A multivariate analysis showed that age, the presence of child siblings at home and day care attendance covariates were strongly associated with S. pneumoniae carriage. In conclusion, over 7 years of vaccination with PCV7 and very high coverage in the last 4 years has led to low carriage prevalence in the first year of life rapidly increasing in the following years and high prevalence of non-PCV7 serotypes carriage.

Carriage of Streptoccoccus pneumoniae in healthy adults aged 60 years or over in a population with very high and long-lasting pneumococcal conjugate vaccine coverage in children: rationale and perspectives for PCV13 implementation.

A serial cross-sectional study of nasopharyngeal carriage among adults aged 60 y or over was conducted in winter-spring 2012 with the aim to describe circulating Streptococcus pneumoniae in an area, Liguria Administrative Region, where the vaccine was implemented for a decade and coverage in pediatric age group reached a value close to 100% for more than 5 y, determining a picture of very high vaccine immunological pressure. The serotype-specific carriage picture in adults was compared with that observed in children by means of a cross-sectional study performed one year before using the same sampling and laboratory methods. Cluster sampling enrolled 283 adults, representative of the open population. Detection of multi-serotype carriage was performed using, real-time PCR and primer specific PCRs. Carriage prevalence of participants with at least one positive sample adjusted for age, i.e., period prevalence, was 18.7%, considering the Ligurian population as standard population, showing that the pneumococcal carriage in the elderly is not a rare event as emerged in other surveys. The long-term use of PCV7 has resulted in strong decrease of vaccine types carriage among adults and children. A multivariate analysis showed that age class and contact with children attending day care covariates were strongly associated with Streptococcus pneumoniae carriage. A strong link between the picture observed in < 5-y-old children and ≥ 60-y-old adults emerged: a strong correlation of specific-serotype prevalence between adults and children and risk factor analysis supported the role played by inter-age-group transmission.

Phase 4 randomized trial of intradermal low-antigen-content inactivated influenza vaccine vs. standard-dose intramuscular vaccine in HIV-1-infected adults

This study evaluated safety, tolerability and immunogenicity of intradermal (ID) trivalent inactivated split influenza vaccine, with a lower antigen content (9 µg HA per strain) than the conventional intramuscular one (15 µg), in HIV-1-infected adults younger than 60 y. A total of 54 HIV-1-positive participants were enrolled and randomly assigned to receive a single dose of either ID-administered low-antigen-content split inactivated vaccine or intramuscularly-administered (IM) standard-dose inactivated split vaccine. Subjects were provided with a diary to monitor any local and/or systemic reactions to the vaccine for 7 d following vaccination. Serum samples were collected before, 28 d and 90 d after immunization. The plasma HIV-RNA and CD4+ T-lymphocyte count were checked at day 0 and day 90. Serum hemagglutination-inhibition (HI) activity for the three influenza strains included in the vaccine composition was measured to assess the antibody response at one month and 3 mo after vaccination. Both vaccines showed optimal safety and tolerability profiles. All the three Committee for Medicinal Products for Human Use immunogenicity criteria for vaccine approval in adults younger than 60 were met by both vaccines against A(H1N1) and A(H3N2) viruses. Both vaccines met mean-fold-increase and seroprotection criteria but failed seroconversion criteria against B virus. No difference in terms of post-vaccination geometric mean titers, mean fold increase, seroprotection and seroconversion rates were found comparing ID and IM vaccines. In conclusion, the recently available low-antigen-content ID vaccine is safe, well-tolerated and as immunogenic as IM standard-dose influenza vaccine.