Cost-effectiveness of introducing the 10-valent pneumococcal conjugate vaccine into the universal immunisation of infants in Brazil

Background Cost-effectiveness studies have been increasingly part of decision processes for incorporating new vaccines into the Brazilian National Immunisation Program. This study aimed to evaluate the cost-effectiveness of 10-valent pneumococcal conjugate vaccine (PCV10) in the universal childhood immunisation programme in Brazil. Methods A decision-tree analytical model based on the ProVac Initiative pneumococcus model was used, following 25 successive cohorts from birth until 5 years of age. Two strategies were compared: (1) status quo and (2) universal childhood immunisation programme with PCV10. Epidemiological and cost estimates for pneumococcal disease were based on National Health Information Systems and literature. A 'top-down' costing approach was employed. Costs are reported in 2004 Brazilian reals. Costs and benefits were discounted at 3%. Results 25 years after implementing the PCV10 immunisation programme, 10 226 deaths, 360 657 disability-adjusted life years (DALYs), 433 808 hospitalisations and 5 117 109 outpatient visits would be avoided. The cost of the immunisation programme would be R$10 674 478 765, and the expected savings on direct medical costs and family costs would be R$1 036 958 639 and R$209 919 404, respectively. This resulted in an incremental cost-effectiveness ratio of R$778 145/death avoided and R$22 066/DALY avoided from the society perspective. Conclusion The PCV10 universal infant immunisation programme is a cost-effective intervention (1-3 GDP per capita/DALY avoided). Owing to the uncertain burden of disease data, as well as unclear long-term vaccine effects, surveillance systems to monitor the long-term effects of this programme will be essential.

Effectiveness of the polysaccharide pneumococcal vaccine among HIV-infected persons in Brazil: a case control study

Abstract Background Polysaccharide pneumococcal vaccine is recommended for use in HIV-infected adults in Brazil but there is uncertainty about its effectiveness in this patient population. The main objective of this study was to assess the effectiveness of the 23-valent polysaccharide pneumococcal vaccine against invasive pneumococcal infection among HIV-infected adult patients in São Paulo, Brazil. Methods A case-control study of 79 cases and 242 controls matched on CD4+ cell count and health care setting was conducted. Among HIV-infected adults in São Paulo, Brazil, with and without S. pneumoniae recovered from a normally sterile site; prior receipt of 23 valent polysaccharide pneumococcal vaccine was determined by review of medical records and patient interview. Results After adjustment for confounding factors, the point estimate for the effectiveness of 23 valent polysaccharide vaccine among HIV-infected adults against all invasive pneumococcal infection was 18% (95% CI: <0 to 62%). Conclusion We were unable to demonstrate a statistically significant protective effect of 23 valent polysaccharide against invasive pneumococcal infection vaccine among HIV-infected adults in Brazil. While the vaccine is relatively inexpensive and safe, its effectiveness among HIV-infected adults in Brazil is uncertain.

Clinical decisions related to CBC screening of asymptomatic full-term infants at risk for group B streptococcus disease

Objective. Although complete blood count (CBC) changes occur with the development of clinical sepsis in newborns, the CBC has not been reported to be a sensitive predictor of sepsis in asymptomatic full-term newborn infants, nor has it been reported to be related to risk factors for sepsis or clinical decisions. The objective of this study was to evaluate the relationship between the WBC/I:T (immature:total neutrophil) ratio and maternal group B streptococcal (GBS) risk factors (rupture of membranes ≥18 hours, maternal temperature ≥100.4°F, maternal age ≤20 years, previous infant with invasive GBS disease, maternal GBS bacteriuria, and black ethnicity); and to evaluate the relationship between the WBC/I:T ratios and providers' clinical decisions (observe versus repeat the CBC or complete sepsis evaluation) in the asymptomatic full-term newborn at risk for early-onset GBS sepsis. ^ Methods. Medical records of infants admitted to the well baby nursery at a tertiary care teaching hospital in Houston, TX between 1/1/99 and 12/31/00 whose gestational ages were ≥35 weeks; who had mothers with GBS positive or unknown culture status and inadequate intrapartum antibiotic prophylaxis; and who had screening CBCs performed in the first 30 hours of life because of GBS risk were reviewed (n = 412). Demographic information, maternal GBS risk factors, CBC results, clinical decisions, and rationales for clinical decisions were collected. ^ Results. With the exception of black ethnicity (p = .0000, odds ratio = 0.213), no statistically significant differences in risk factors between infants with normal and abnormal WBC counts or normal and abnormal I:T ratios were found. Infants with abnormal WBCs had a significantly higher likelihood of having a CBC repeated (p = 0.002 for WBC). Providers documented the CBC result in the rationale for clinical decisions in 62% of the cases. ^ Conclusion. The CBC results were not related to maternal risk factors for GBS except for ethnicity. Black infants had significantly lower WBC levels than infants of other ethnicities, although this difference was clinically insignificant. Infants with abnormal WBCs had a significantly higher likelihood of undergoing repeat CBCs but not sepsis evaluations. Provider rationale was difficult to evaluate due to insufficient documentation. The screening CBC result did not impact the clinicians' decisions to initiate sepsis evaluations in this population. ^

Serotype/serogroup-specific antibiotic non-susceptibility of invasive and non-invasive Streptococcus pneumoniae, Switzerland, 2004 to 2014.

Concurrent analysis of antibiotic resistance of colonising and invasive Streptococcus pneumoniae gives a more accurate picture than looking at either of them separately. Therefore, we analysed 2,129 non-invasive and 10,996 invasive pneumococcal isolates from Switzerland from 2004 to 2014, which spans the time before and after the introduction of the heptavalent (PCV7) and 13-valent (PCV13) conjugated pneumococcal polysaccharide vaccines. Serotype/serogroup information was linked with all antibiotic resistance profiles. During the study period, the proportion of non-susceptible non-invasive and invasive isolates significantly decreased for penicillin, ceftriaxone, erythromycin and trimethoprim/sulfamethoxazole (TMP-SMX). This was most apparent in non-invasive isolates from study subjects younger than five years (penicillin (p = 0.006), erythromycin (p = 0.01) and TMP-SMX (p = 0.002)). Resistant serotypes/serogroups included in PCV7 and/or PCV13 decreased and were replaced by non-PCV13 serotypes (6C and 15B/C). Serotype/serogroup-specific antibiotic resistance rates were comparable between invasive and non-invasive isolates. Adjusted odds ratios of serotype/serogroup-specific penicillin resistance were significantly higher in the west of Switzerland for serotype 6B (1.8; 95% confidence interval (CI): 1.4-4.8), 9V (3.4; 95% CI: 2.0-5.7), 14 (5.3; 95% CI: 3.8-7.5), 19A (2.2; 95% CI: 1.6-3.1) and 19F (3.1; 95% CI: 2.1-4.6), probably due to variations in the antibiotic consumption.

Variations in chemoprophylaxis for meningococcal disease: a retrospective case note review, analysis of routine prescribing data and questionnaire of general practitioners

BACKGROUND: Invasive meningococcal disease is a significant cause of mortality and morbidity in the UK. Administration of chemoprophylaxis to close contacts reduces the risk of a secondary case. However, unnecessary chemoprophylaxis may be associated with adverse reactions, increased antibiotic resistance and removal of organisms, such as Neisseria lactamica, which help to protect against meningococcal disease. Limited evidence exists to suggest that overuse of chemoprophylaxis may occur. This study aimed to evaluate prescribing of chemoprophylaxis for contacts of meningococcal disease by general practitioners and hospital staff. METHODS: Retrospective case note review of cases of meningococcal disease was conducted in one health district from 1st September 1997 to 31st August 1999. Routine hospital and general practitioner prescribing data was searched for chemoprophylactic prescriptions of rifampicin and ciprofloxacin. A questionnaire of general practitioners was undertaken to obtain more detailed information. RESULTS: Prescribing by hospital doctors was in line with recommendations by the Consultant for Communicable Disease Control. General practitioners prescribed 118% more chemoprophylaxis than was recommended. Size of practice and training status did not affect the level of additional prescribing, but there were significant differences by geographical area. The highest levels of prescribing occurred in areas with high disease rates and associated publicity. However, some true close contacts did not appear to receive prophylaxis. CONCLUSIONS: Receipt of chemoprophylaxis is affected by a series of patient, doctor and community interactions. High publicity appears to increase demand for prophylaxis. Some true contacts do not receive appropriate chemoprophylaxis and are left at an unnecessarily increased risk

One-step homogeneous C-reactive protein assay for saliva

Background: Cardiovascular disease is the leading cause of death in the world. Human C-reactive protein (CRP) has been used in the risk assessment of coronary events. Human saliva mirrors the body's health and well-being and is non-invasive, easy to collect and ideal for third world countries as well as for large patient screening. The aim was to establish a saliva CRP reference range and to demonstrate the clinical utility of salivary CRP levels in assessing the coronary events in a primary health care setting. Methods: We have used a homogeneous bead based assay to detect CRP levels in human saliva. We have developed a rapid 15 min (vs 90 min), sequential, one-step assay to detect CRP in saliva. Saliva was collected from healthy volunteers (n = 55, ages 20-70 years) as well as from cardiac patients (n = 28, ages 43-86 years). Results: The assay incubation time was optimised from 90 min to 15 mm and generated a positive correlation (n = 29, range 10-2189 pg/mL, r2 = 0.94; Passing Bablok slope 0.885. Intercept 0, p>0.10), meaning we could decrease the incubation time and produce equivalent results with confidence. The mean CRP level in the saliva of healthy human volunteers was 285 pg/mL and in cardiac patients was 1680 pg/mL (p<0.01). Analysis of CRP concentrations in paired serum and saliva samples from cardiac patients gave a positive correlation (r2 = 0.84, p<0.001) and the salivary CRP concentration capable of distinguishing healthy from diseased patients. Conclusions: The results suggest that this minimally invasive, rapid and sensitive assay will be useful in large patient screening studies for risk assessment of coronary events. (C) 2011 Elsevier B.V. All rights reserved.

A Global Crisis for Seagrass Ecosystems

Seagrasses, marine flowering plants, have a long evolutionary history but are now challenged with rapid environmental changes as a result of coastal human population pressures. Seagrasses provide key ecological services, including organic carbon production and export, nutrient cycling, sediment stabilization, enhanced biodiversity, and trophic transfers to adjacent habitats in tropical and temperate regions. They also serve as “coastal canaries,” global biological sentinels of increasing anthropogenic influences in coastal ecosystems, with large-scale losses reported worldwide. Multiple stressors, including sediment and nutrient runoff, physical disturbance, invasive species, disease, commercial fishing practices, aquaculture, overgrazing, algal blooms, and global warming, cause seagrass declines at scales of square meters to hundreds of square kilometers. Reported seagrass losses have led to increased awareness of the need for seagrass protection, monitoring, management, and restoration. However, seagrass science, which has rapidly grown, is disconnected from public awareness of seagrasses, which has lagged behind awareness of other coastal ecosystems. There is a critical need for a targeted global conservation effort that includes a reduction of watershed nutrient and sediment inputs to seagrass habitats and a targeted educational program informing regulators and the public of the value of seagrass meadows.

WHO guidelines for antimicrobial treatment in children admitted to hospital in an area of intense Plasmodium falciparum transmission: prospective study.

OBJECTIVES: To assess the performance of WHO's "Guidelines for care at the first-referral level in developing countries" in an area of intense malaria transmission and identify bacterial infections in children with and without malaria. DESIGN: Prospective study. SETTING: District hospital in Muheza, northeast Tanzania. PARTICIPANTS: Children aged 2 months to 13 years admitted to hospital for febrile illness. MAIN OUTCOME MEASURES: Sensitivity and specificity of WHO guidelines in diagnosing invasive bacterial disease; susceptibility of isolated organisms to recommended antimicrobials. RESULTS: Over one year, 3639 children were enrolled and 184 (5.1%) died; 2195 (60.3%) were blood slide positive for Plasmodium falciparum, 341 (9.4%) had invasive bacterial disease, and 142 (3.9%) were seropositive for HIV. The prevalence of invasive bacterial disease was lower in slide positive children (100/2195, 4.6%) than in slide negative children (241/1444, 16.7%). Non-typhi Salmonella was the most frequently isolated organism (52/100 (52%) of organisms in slide positive children and 108/241 (45%) in slide negative children). Mortality among children with invasive bacterial disease was significantly higher (58/341, 17%) than in children without invasive bacterial disease (126/3298, 3.8%) (P<0.001), and this was true regardless of the presence of P falciparum parasitaemia. The sensitivity and specificity of WHO criteria in identifying invasive bacterial disease in slide positive children were 60.0% (95% confidence interval 58.0% to 62.1%) and 53.5% (51.4% to 55.6%), compared with 70.5% (68.2% to 72.9%) and 48.1% (45.6% to 50.7%) in slide negative children. In children with WHO criteria for invasive bacterial disease, only 99/211(47%) of isolated organisms were susceptible to the first recommended antimicrobial agent. CONCLUSIONS: In an area exposed to high transmission of malaria, current WHO guidelines failed to identify almost a third of children with invasive bacterial disease, and more than half of the organisms isolated were not susceptible to currently recommended antimicrobials. Improved diagnosis and treatment of invasive bacterial disease are needed to reduce childhood mortality.

Clinical effectiveness of posaconazole versus fluconazole as antifungal prophylaxis in hematology-oncology patients: a retrospective cohort study.

In preventing invasive fungal disease (IFD) in patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS), clinical trials demonstrated efficacy of posaconazole over fluconazole and itraconazole. However, effectiveness of posaconazole has not been investigated in the United States in real-world setting outside the environment of controlled clinical trial. We performed a single-center, retrospective cohort study of 130 evaluable patients ≥18 years of age admitted to Duke University Hospital between 2004 and 2010 who received either posaconazole or fluconazole as prophylaxis during first induction or first reinduction chemotherapy for AML or MDS. The primary endpoint was possible, probable, or definite breakthrough IFD. Baseline characteristics were well balanced between groups, except that posaconazole recipients received reinduction chemotherapy and cytarabine more frequently. IFD occurred in 17/65 (27.0%) in the fluconazole group and in 6/65 (9.2%) in the posaconazole group (P = 0.012). Definite/probable IFDs occurred in 7 (10.8%) and 0 patients (0%), respectively (P = 0.0013). In multivariate analysis, fluconazole prophylaxis and duration of neutropenia were predictors of IFD. Mortality was similar between groups. This study demonstrates superior effectiveness of posaconazole over fluconazole as prophylaxis of IFD in AML and MDS patients. Such superiority did not translate to reductions in 100-day all-cause mortality.

Characterization of the FKBP12-Encoding Genes in Aspergillus fumigatus.

Invasive aspergillosis, largely caused by Aspergillus fumigatus, is responsible for a growing number of deaths among immunosuppressed patients. Immunosuppressants such as FK506 (tacrolimus) that target calcineurin have shown promise for antifungal drug development. FK506-binding proteins (FKBPs) form a complex with calcineurin in the presence of FK506 (FKBP12-FK506) and inhibit calcineurin activity. Research on FKBPs in fungi is limited, and none of the FKBPs have been previously characterized in A. fumigatus. We identified four orthologous genes of FKBP12, the human FK506 binding partner, in A. fumigatus and designated them fkbp12-1, fkbp12-2, fkbp12-3, and fkbp12-4. Deletional analysis of the four genes revealed that the Δfkbp12-1 strain was resistant to FK506, indicating FKBP12-1 as the key mediator of FK506-binding to calcineurin. The endogenously expressed FKBP12-1-EGFP fusion protein localized to the cytoplasm and nuclei under normal growth conditions but also to the hyphal septa following FK506 treatment, revealing its interaction with calcineurin. The FKBP12-1-EGFP fusion protein didn't localize at the septa in the presence of FK506 in the cnaA deletion background, confirming its interaction with calcineurin. Testing of all deletion strains in the Galleria mellonella model of aspergillosis suggested that these proteins don't play an important role in virulence. While the Δfkbp12-2 and Δfkbp12-3 strains didn't show any discernable phenotype, the Δfkbp12-4 strain displayed slight growth defect under normal growth conditions and inhibition of the caspofungin-mediated "paradoxical growth effect" at higher concentrations of the antifungal caspofungin. Together, these results indicate that while only FKBP12-1 is the bona fide binding partner of FK506, leading to the inhibition of calcineurin in A. fumigatus, FKBP12-4 may play a role in basal growth and the caspofungin-mediated paradoxical growth response. Exploitation of differences between A. fumigatus FKBP12-1 and human FKBP12 will be critical for the generation of fungal-specific FK506 analogs to inhibit fungal calcineurin and treat invasive fungal disease.

Development of selective media for the isolation of yeasts and filamentous fungi from the sputum of adult patients with cystic fibrosis (CF)

Yeasts and filamentous fungi are beginning to emerge as significant microbial pathogens in patients with cystic fibrosis (CF), particularly in relation to allergic-type responses, as seen in patients with allergic bronchopulmonary aspergillosis (ABPA), Aspergillus bronchitis and in invasive fungal disease in lung transplant patients. Four fungal media were compared in this study, including Sabouraud Dextrose Agar (SDA) and Medium B, with and without the addition of selective antibiotics, where antibiotic-supplemented media were designated with (+). These media were compared for their ability to suppress contaminating, mainly Gram-ve pathogens, in CF sputa (Pseudomonas aeruginosa, Burkholderia cepacia complex [BCC] organisms) and to enhance the growth of fungi present in CF sputum. Medium B consisted of glucose (16.7 g/l), agar (20 g/l), yeast extract (30 g/l) and peptone (6.8 g/l) at pH 6.3 and both SDA(+) and Medium B+ were supplemented with cotrimethoxazole, 128 mg/l; chloramphenicol, 50 mg/l; ceftazidime, 32 mg/l; colistin, 24 mg/l). Employment of SDA(+) or Medium B+ allowed an increase in specificity in the detection of yeasts and moulds, by 42.8% and 39.3%, respectively, over SDA when used solely. SDA(+) had a greater ability than Medium B+ to suppress bacterial growth from predominantly Gram-ve co-colonisers. This is a significant benefit when attempting to detect and isolate fungi from the sputum of CF patients, as it largely suppressed any bacterial growth, with the exception of the BCC organisms, thus allowing for an increased opportunity to detect target fungal organisms in sputum and represented a significant improvement over the commercial medium (SDA), which is currently used. Overall, both novel selective media were superior in their ability to suppress bacteria in comparison with the commercially available SDA medium, which is routinely employed in most clinical microbiology diagnostic laboratories presently. Alternatively, Medium B+ had a great ability to grow fungi than SDA(+) and when employed together, the specificity of combined use was 82%, with a sensitivity for yeasts, filamentous fungi, and combined overall fungi of 96.0%, 92.3% and 96.0%, respectively. Overall, when employing one fungal selective medium for the routine detection of yeasts and filamentous fungi in the sputum of CF patients, we would recommend employment of Medium B+. However, we would recommend the combined employment of SDA(+) and Medium B+, in order to synergistically isolate and detect the greatest number of fungi present in CF sputa. (C) 2008 European Cystic Fibrosis Society. Published by Elsevier B.V All rights reserved.

Epidemiological studies of Streptococcus pneumoniae carriage in the post-vaccination era among two risk groups: children and the elderly

Dissertation presented to obtain the Ph.D. degree in Biology/ Molecular Biology

Enfermedad neonatal temprana por Streptococcus Agalactiae en un unidad de recién nacidos, factores de riesgo maternofetales asocaidos a severidad y mortalidad

la colonización materna por estreptococo del grupo B (SGB) en países en desarrollo es de 4-20%, 50% de sus hijos nacen colonizados y el 1-2% desarrollan enfermedad invasiva con alto riesgo de morbimortalidad y secuelas. La incidencia de infección es diez veces más alta en menores de 1500gramos. Objetivo: determinar los factores de riesgo maternofetales asociados a enfermedad severa y mortalidad neonatal por Streptococcus agalactidae en una unidad de recién nacidos. Materiales y Métodos: se realizó un estudio observacional analítico de cohorte histórica durante un periodo de 2 años. Se tomaron 11 (once) recién nacidos con cuadro clínico de enfermedad invasiva por SGB, con confirmación en ocho (8) casos con hemocultivos, un (1) caso con cultivo de líquido cefalorraquídeo y dos (2) con ambos. Quince (15) controles que correspondían a las madres colonizadas con recién nacidos asintomáticos y con cultivos negativos. Las características demográficas de los dos (2) grupos no mostraron diferencias significativas. Se calcularon frecuencias absolutas y relativas y se buscaron asociaciones mediante el cálculo del estadístico Chi2, se aceptaron valores de p < 0.05, bajo el programa SPSS 15.0 para Windows. Resultados: los factores maternos predictivos para enfermedad por SGB incluyeron, fiebre periparto mayor a 37.5 grados centígrados (p <0.05), corioamnionitis y ruptura de membranas mayor a 18 horas (p<0.05). Los factores de riesgo neonatal incluyeron prematurez (<37 semanas) y bajo peso al nacer(<2500 gramos) (p<0.05). La severidad de la enfermedad se valoró por la presencia de neumonía, meningitis o hemorragia pulmonar. Se encontró una mortalidad de 5(45%). Conclusiones: se encontró relación estadísticamente significativa entre la corioaminionitis materna, la ruptura de membranas mayor a 18 horas, la prematurez y el peso bajo al nacer con la severidad de la enfermedad y la mortalidad. La incidencia estimada de infección neonatal en la unidad de recién nacidos fue de 1,8 casos/1000 nacidos vivos y la de colonización materna fue de 4,3 casos/ 1000 maternas. Se deben realizar más estudios en el país para establecer la incidencia real de enfermedad neonatal por SGB y hacer investigación sobre la costoefectividad de las medidas de prevención.

Adherence and intracellular parasitism of Paracoccidioides brasiliensis in Vero cells

Paracoccidioides brasiliensis is a dimorphic fungus known to produce invasive systemic disease in humans. The 43-kDa glycoprotein of P, brasiliensis is the major diagnostic antigen of paracoccidioidomycosis and may act as a virulence factor, since it is a receptor for laminin. Very little is known about early interact-ions between this fungus and the host cells, so we developed in vitro a model system employing cultured mammalian cells (Vero cells), in order to investigate the factors and virulence mechanisms of P. brasiliensis related to the adhesion and invasion process. We found that there is a permanent interaction after 30 min of contact between the fungus and the cells. The yeasts multiply in the cells for between 5 and 24 h. Different strains of P, brasiliensis were compared, and strain 18 thigh virulence) was the most strongly adherent, followed by strain 113 (virulent), 265 (considered of low virulence) and 113M(mutant obtained by ultraviolet radiation, deficient in gp43). P. brasiliensis adhered to the epithelial cells by a narrow tube, while depressions were noticed in the cell surface, suggesting an active cavitation process. An inhibition assay was performed and it was verified that anti-gp43 serum and a pool of sera from individuals with paracoccidioidomycosis were able to inhibit the adhesion of P. brasiliensis to the Vero cells. Glycoprotein 43 (gp43) antiserum abolished 85 % of the binding activity of P. brasiliensis. This fungus can also invade the Vero cells, and intraepithelial parasitism could be an escape mechanism in paracoccidioidomycosis. (C) 2000 Editions scientifiques et medicales Elsevier SAS.

Therapeutic DNA Vaccine Encoding Peptide P10 against Experimental Paracoccidioidomycosis

Paracoccidioidomycosis (PCM), caused by Paracoccidioides brasiliensis, is the most prevalent invasive fungal disease in South America. Systemic mycoses are the 10th most common cause of death among infectious diseases in Brazil and PCM is responsible for more than 50% of deaths due to fungal infections. PCM is typically treated with sulfonamides, amphotericin B or azoles, although complete eradication of the fungus may not occur and relapsing disease is frequently reported. A 15-mer peptide from the major diagnostic antigen gp43, named P10, can induce a strong T-CD4+ helper-1 immune response in mice. The TEPITOPE algorithm and experimental data have confirmed that most HLA-DR molecules can present P10, which suggests that P10 is a candidate antigen for a PCM vaccine. In the current work, the therapeutic efficacy of plasmid immunization with P10 and/or IL-12 inserts was tested in murine models of PCM. When given prior to or after infection with P. brasiliensis virulent Pb 18 isolate, plasmid-vaccination with P10 and/or IL-12 inserts successfully reduced the fungal burden in lungs of infected mice. In fact, intramuscular administration of a combination of plasmids expressing P10 and IL-12 given weekly for one month, followed by single injections every month for 3 months restored normal lung architecture and eradicated the fungus in mice that were infected one month prior to treatment. The data indicate that immunization with these plasmids is a powerful procedure for prevention and treatment of experimental PCM, with the perspective of being also effective in human patients.