High Protein Binding and Cidal Activity against Penicillin-Resistant S. pneumoniae: A Cefditoren In Vitro Pharmacodynamic Simulation

BACKGROUND: Although protein binding is a reversible phenomenon, it is assumed that antibacterial activity is exclusively exerted by the free (unbound) fraction of antibiotics. METHODOLOGY/PRINCIPAL FINDINGS: Activity of cefditoren, a highly protein bound 3(rd) generation cephalosporin, over 24h after an oral 400 mg cefditoren-pivoxil bid regimen was studied against six S. pneumoniae strains (penicillin/cefditoren MICs; microg/ml): S1 (0.12/0.25), S2 (0.25/0.25), S3 and S4 (0.5/0.5), S5 (1/0.5) and S6 (4/0.5). A computerized pharmacodynamic simulation with media consisting in 75% human serum and 25% broth (mean albumin concentrations = 4.85+/-0.12 g/dL) was performed. Protein binding was measured. The cumulative percentage of a 24h-period that drug concentrations exceeded the MIC for total (T > MIC) and unbound concentrations (fT > MIC), expressed as percentage of the dosing interval, were determined. Protein binding was 87.1%. Bactericidal activity (> or = 99.9% initial inocula reduction) was obtained against strains S1 and S2 at 24h (T > MIC = 77.6%, fT > MIC = 23.7%). With T > MIC of 61.6% (fT > MIC = 1.7%), reductions against S3 and S4 ranged from 90% to 97% at 12h and 24h; against S5, reduction was 45.1% at 12h and up to 85.0% at 24h; and against S6, reduction was 91.8% at 12h, but due to regrowth of 52.9% at 24h. Cefditoren physiological concentrations exerted antibacterial activity against strains exhibiting MICs of 0.25 and 0.5 microg/ml under protein binding conditions similar to those in humans. CONCLUSIONS/SIGNIFICANCE: The results of this study suggest that, from the pharmacodynamic perspective, the presence of physiological albumin concentrations may not preclude antipneumococcal activity of highly bound cephalosporins as cefditoren

Sex- and age-specific trends in mortality from suicide and undetermined death in Germany 1991–2002

BACKGROUND: Over the last decade, significant downward linear time trends in suicide mortality were observed in most Western countries. To date, it is not established whether those favourable time trends developed homogeneously for sex and age groups and how they were affected by the number of undetermined deaths. METHODS: Data on suicide mortality and undetermined death from 1991 to 2002 in Germany were obtained from the German Federal Statistical Office. For each year, the age-standardised suicide rate (SR), undetermined death rate (UDR) and total rate (SR+UDR) was calculated by direct standardisation separately for men and women. Time trends were analyzed by Poisson regression estimating the average annual percentage change (AAPC) of the rates for sex and four age groups (15–24, 25–44, 45–74, ≥ 75 years). RESULTS: A significant decline of the SR was observed in all age groups but was less pronounced among the younger ages, particularly among men aged 15–24 years (AAPC -0.7%, p = 0.041). The SR in the oldest male age group (≥ 75 years) declined much stronger (AAPC -3.5%, p < 0.001). In women, the AAPC of the SR ranged from -1.7% to -4.6%. The average annual percentage changes in the age groups 25 – 74 years did not differ substantially for SR and SR+UDR. In contrast, due to an increase of undetermined deaths for subjects ≥ 75 years, time trends in this age group were affected by the number of undetermined deaths, especially in women. CONCLUSION: Observing downward trends in suicide mortality with lower declines for younger subjects, prevention strategies should focus in particular on younger subjects

What Does It Drive the Relationship Between Suicides and Economic Conditions? New Evidence from Spain

In this paper we analyse suicides across the 17 Spanish regions over the period 2002?2013. In doing so, we estimate count panel data models considering gender differences taking into account before and during economic crisis periods. A range of aggregate socioeconomic regional-level factors have been considered. Our empirical results show that: (1) a socioeconomic urban?rural suicide differentials exist, (2) there exists a Mediterranean suicide pattern; and (3) unemployment levels have a marked importance during the crisis period. The results of this study may have usefulness for suicide prevention in Spain

Enhanced In Vivo Activity of Cefditoren in Pre-Immunized Mice against Penicillin-Resistant S. pneumoniae (Serotypes 6B, 19F and 23F) in a Sepsis Model

Background Specific antibodies are likely to be present before S. pneumoniae infection. We explored cefditoren (CDN) total and free values of serum concentrations exceeding the MIC (t>MIC) related to efficacy in a mice sepsis model, and the effect of specific gammaglobulins on in-vitro phagocytosis and in-vivo efficacy. Methodology/Principal Findings We used three pneumococcal isolates (serotype, MIC of CDN): Strain 1 (6B, 1 µg/ml), Strain 2 (19F, 2 µg/ml) and Strain 3 (23F, 4 µg/ml). Hyperimmune serum (HS) was obtained from mice immunized with heat-inactivated strains. In-vitro, phagocytosis by HS diluted 1/10 in presence/absence of sub-inhibitory concentrations was measured by flow cytometry including fluorescent bacteria and a neutrophil cell line. In-vivo dose-ranging experiments with HS (dilutions 1/2–1/16) and CDN (6.25 mg/kg–100 mg/kg tid for 48 h) were performed to determine the minimal protective dilution/dose (highest survival) and the non-protective highest dilution/dose (highest mortality: HS-np dilution and CDN-np dose) over 7 days. Efficacy of CDN-np in animals pre-immunized with HS-np (combined strategy) was explored and blood bacterial clearance determined. The CDN measured protein binding was 86.9%. In-vitro, CDN significantly increased phagocytosis (vs. HS 1/10). In non pre-immunized animals, t>MIC values for CDN of ≈35% (total) and ≈19% (free) were associated with 100% survival. Significant differences in survival were found between HS-np alone (≤20%) or CDN-np alone (≤20%) vs. the combined strategy (90%, 60% and 60% for Stains 1, 2 and 3), with t>MIC (total/free) of 22.8%/14.3%, 26.8%/16.0%, and 22.4%/12.7% for Strains 1, 2 and 3, respectively. Prior to the second dose (8 h), median bacterial counts were significantly lower in animals surviving vs. dead at day 7. Conclusions/Significance In mice (CDN protein binding similar to humans) total t>MIC values of ≈35% (≈19% free) were efficacious, with a decrease in the required values in pre-immunized animals. This reinforces that immunoprotection to overcome resistance may provide lifesaving strategies.This study was supported by an unrestricted grant from Tedec-Meiji Farma S.A., Madrid, Spain. Tedec-Meiji Farma S.A. had a role in providing reagents, materials and analysis toolsPeer reviewe

Antibiotic Selection Pressure and Macrolide Resistance in Nasopharyngeal Streptococcus pneumoniae: A Cluster-Randomized Clinical Trial

Jeremy Keenan and colleagues report that during a cluster-randomized clinical trial in Ethiopia, nasopharyngeal pneumococcal resistance to macrolides was significantly higher in communities randomized to receive azithromycin compared with untreated control communities

Suicide in Sri Lanka 1975-2012:age, period and cohort analysis of police and hospital data

BACKGROUND: Sri Lanka has experienced major changes in its suicide rates since the 1970s, and in 1995 it had one of the highest rates in the world. Subsequent reductions in Sri Lanka’s suicide rates have been attributed to the introduction of restrictions on the availability of highly toxic pesticides. We investigate these changes in suicide rates in relation to age, gender, method specific trends and birth-cohort and period effects, with the aim of informing preventative strategies. METHODS: Secular trends of suicide in relation to age, sex, method, birth-cohort and period effects were investigated graphically using police data (1975–2012). Poisoning case-fatality was investigated using national hospital admission data (2004–2010). RESULTS: There were marked changes to the age-, gender- and method-specific incidence of suicide over the study period. Year on year declines in rates began in 17–25 year olds in the early 1980s. Reduction in older age groups followed and falls in all age groups occurred after all class I (the most toxic) pesticides were banned. Distinct changes in the age/gender pattern of suicide are observed: in the 1980s suicide rates were highest in 21–35 year old men; by the 2000s, this pattern had reversed with a stepwise increase in male rates with increasing age. Throughout the study period female rates were highest in 17–25 year olds. There has been a rise in suicide by hanging, though this rise is relatively small in relation to the marked decline in self-poisoning deaths. The patterns of suicides are more consistent with a period rather than birth-cohort effect. CONCLUSIONS: The epidemiology of suicide in Sri Lanka has changed noticeably in the last 30 years. The introduction of pesticide regulations in Sri Lanka coincides with a reduction in suicide rates, with evidence of limited method substitution. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2458-14-839) contains supplementary material, which is available to authorized users