Staphylococcus aureus causes a wide range of diseases from skin infections to life threatening invasive diseases such as bacteremia, endocarditis, pneumonia, surgical site infections, and osteomyelitis. Skin infections such as furuncles, carbuncles, folliculitis, erysipelas, and cellulitis constitute a large majority of infections caused by S. aureus (SA). These infections cause significant morbidity, healthcare costs, and represent a breeding ground for antimicrobial resistance. Furthermore, skin infection with SA is a major risk factor for invasive disease. Here we describe the pre-clinical efficacy of a multicomponent toxoid vaccine (IBT-V02) for prevention of S. aureus acute skin infections and recurrence. IBT-V02 targets six SA toxins including the pore-forming toxins alpha hemolysin (Hla), Panton-Valentine leukocidin (PVL), leukocidin AB (LukAB), and the superantigens toxic shock syndrome toxin-1 and staphylococcal enterotoxins A and B. Immunization of mice and rabbits with IBT-V02 generated antibodies with strong neutralizing activity against toxins included in the vaccine, as well as cross-neutralizing activity against multiple related toxins, and protected against skin infections by several clinically relevant SA strains of USA100, USA300, and USA1000 clones. Efficacy of the vaccine was also shown in non-naïve mice pre-exposed to S. aureus. Furthermore, vaccination with IBT-V02 not only protected mice from a primary infection but also demonstrated lasting efficacy against a secondary infection, while prior challenge with the bacteria alone was unable to protect against recurrence. Serum transfer studies in a primary infection model showed that antibodies are primarily responsible for the protective response.

Development and validation of large animal models of Pseudomonas aeruginosa ventilator-associated pneumonia is needed for testing new drug candidates in a manner mimicking how they will be used clinically. We have developed a new model in which rabbits were ventilated with low-tidal volume and challenged with P. aeruginosa to recapitulate hallmark clinical features of acute respiratory distress syndrome (ARDS): acute lung injury and inflammation, progressive decrease in arterial oxygen partial pressure to fractional inspired oxygen PaO2:FiO2, leukopenia, neutropenia, thrombocytopenia, hyperlactatemia, severe hypotension, bacterial dissemination from lung to other organs, multiorgan dysfunction, and ultimately death. We evaluated the predictive power of this rabbit model for antibiotic efficacy testing by determining whether a humanized dosing regimen of meropenem, a potent antipseudomonal β-lactam antibiotic, when administered with or without intensive care unit (ICU)-supportive care (fluid challenge and norepinephrine), could halt or reverse natural disease progression. Our humanized meropenem dosing regimen produced plasma concentration-time profile in the rabbit model similar to those reported in patients with ventilator-associated bacterial pneumonia. In this rabbit model, treatment with humanized meropenem and ICU-supportive care achieved the highest level of survival, halted the worsening of ARDS biomarkers and reversed lethal hypotension, although treatment with humanized meropenem alone also conferred some protection when compared to treatment with placebo (saline) alone or placebo plus ICU-supportive care. In conclusion, this rabbit model could help predict whether an antibiotic will be efficacious for the treatment of human ventilator-associated pneumonia.

Molecular epidemiology and clinical impact of human rhinovirus (HRV) are not well documented in tropical regions. This study compared the clinical characteristics of HRV to other common viral infections and investigated the molecular epidemiology of HRV in hospitalized children with acute respiratory infections (ARIs) in Vietnam. From April 2010 to May 2011, 1082 nasopharyngeal swabs were screened for respiratory viruses by PCR. VP4/VP2 sequences of HRV were further characterized. HRV was the most commonly detected virus (30%), in which 70% were diagnosed as either pneumonia or bronchiolitis. Children with single HRV infections presented with significantly higher rate of hypoxia than those infected with respiratory syncytial virus or parainfluenza virus (PIV)-3 (12·4% vs. 3·8% and 0%, respectively, P < 0·05), higher rate of chest retraction than PIV-1 (57·3% vs. 34·5%, P = 0·028), higher rate of wheezing than influenza A (63·2% vs. 42·3%, P = 0·038). HRV-C did not differ to HRV-A clinically. The genetic diversity and changes of types over time were observed and may explain the year-round circulation of HRV. One novel HRV-A type was discovered which circulated locally for several years. In conclusion, HRV showed high genetic diversity and was associated with significant morbidity and severe ARIs in hospitalized children.

Staphylococcus aureus is a major human pathogen that causes a wide range of infections by producing an arsenal of cytotoxins. We found that passive immunization with either a monoclonal antibody (MAb) neutralizing alpha-hemolysin or a broadly cross-reactive MAb neutralizing Panton-Valentine leukocidin, leukocidin ED, and gamma-hemolysins HlgAB and HlgCB conferred only partial protection, whereas the combination of those two MAbs conferred significant protection in a rabbit model of necrotizing pneumonia caused by the USA300 methicillin-resistant S. aureus epidemic clone.

Information about viral acute respiratory infections (ARIs) is essential for prevention, diagnosis and treatment, but it is limited in tropical developing countries. This study described the clinical and epidemiological characteristics of ARIs in children hospitalized in Vietnam. Nasopharyngeal samples were collected from children with ARIs at Ho Chi Minh City Children's Hospital 2 between April 2010 and May 2011 in order to detect respiratory viruses by polymerase chain reaction. Viruses were found in 64% of 1082 patients, with 12% being co-infections. The leading detected viruses were human rhinovirus (HRV; 30%), respiratory syncytial virus (RSV; 23·8%), and human bocavirus (HBoV; 7·2%). HRV was detected all year round, while RSV epidemics occurred mainly in the rainy season. Influenza A (FluA) was found in both seasons. The other viruses were predominant in the dry season. HRV was identified in children of all age groups. RSV, parainfluenza virus (PIV) 1, PIV3 and HBoV, and FluA were detected predominantly in children aged 24 months, respectively. Significant associations were found between PIV1 with croup (P < 0·005) and RSV with bronchiolitis (P < 0·005). HBoV and HRV were associated with hypoxia (P < 0·05) and RSV with retraction (P < 0·05). HRV, RSV, and HBoV were detected most frequently and they may increase the severity of ARIs in children.

In a rabbit model of methicillin-resistant S. aureus prosthetic joint infection, prophylaxis with AZD6389*—a combination of three monoclonal antibodies targeting alpha-hemolysin, bicomponent cytotoxins (LukSF/LukED/HlgAB/HlgCB), and clumping factor A—resulted in significant reductions in joint swelling, erythema, intra-articular pus, and bacterial burden in synovial tissues and biofilm-associated prosthetic implants when compared with isotype-matched control IgG. Targeting specific staphylococcal virulence factors could thus have potential clinical utility for prevention of prosthetic joint infection.

Scope: Energy deficit is a common characteristic of neurodegenerative disorders, including Alzheimer's disease. Adenosine monophosphate activated protein kinase (AMPK) is a key enzyme maintaining energy balance by regulating the cellular uptake of glucose, β-oxidation of fatty acids, and expression of glucose transporter 4. Since resveratrol has been shown to increase the activity of AMPK, we hypothesized that it might influence energy metabolism in a model neuron-like cell line, murine Neuro2a cells.Methods and results: Resveratrol caused an elevation of adenosine triphosphate (ATP) and guanosine triphosphate (GTP) in a dose-dependent manner. The highest ATP and GTP levels achieved by treatment with resveratrol were 70.3 ± 8.2 nmol/mg protein (1.9-fold of control) and 27.2 ± 4.0 nmol/mg protein (1.7-fold of control), respectively, when cells were treated with 100 μM resveratrol for 6 h. Interestingly, increases in the total sum of all adenine nucleotides were found upon addition of resveratrol. Despite these increases in ATP, GTP, and the total adenine nucleotide pool, resveratrol treatment led to a decrease in glucose consumption and lactate release, suggesting that resveratrol does not increase energy production (e.g. via AMPK kinase activation) but rather inhibits energy-consuming processes.Conclusion: Resveratrol increases the levels of ATP and GTP, but without creating an additional glucose demand. treated with 100 µM resveratrol for 6 h. Interestingly, substantial increases in the total sum of all adenine nucleotides were found upon addition of resveratrol. Despite these increases in ATP, GTP and the total adenine nucleotide pool, resveratrol treatment led to a pronounced decrease in glucose consumption and lactate release, suggesting that resveratrol does not increase energy production (e.g. via AMPK kinase activation) but rather inhibits energy consuming processes.Conclusions: Resveratrol increases the levels of free high-energy nucleotides, including ATP and GTP, but without creating an additional glucose demand.4

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