Arginine vasopressin receptor 2 activation promotes microvascular permeability in sepsis.

Methicillin-resistant Staphylococcus aureus (MRSA) sepsis is a severe condition associated with vascular leakage and poor prognosis. The hemodynamic management of sepsis targets hypotension, but there is no specific treatment available for vascular leakage. Arginine vasopressin (AVP) has been used in sepsis to promote vasoconstriction by activating AVP receptor 1 (V1R). However, recent evidence suggests that increased fluid retention may be associated with the AVP receptor 2 (V2R) activation worsening the outcome of sepsis. Hence, we hypothesized that the inhibition of V2R activation ameliorates the severity of microvascular hyperpermeability during sepsis. The hypothesis was tested using a well-characterized and clinically relevant ovine model of MRSA pneumonia/sepsis and in vitro assays of human lung microvascular endothelial cells (HMVECs). in vivo experiments demonstrated that the treatment of septic sheep with tolvaptan (TLVP), an FDA-approved V2R antagonist, significantly attenuated the sepsis-induced fluid retention and markedly reduced the lung water content. These pathological changes were not affected by the treatment with V2R agonist, desmopressin (DDAVP). Additionally, the incubation of cultured HMVECs with DDAVP, and DDAVP along with MRSA significantly increased the paracellular permeability. Finally, both the DDAVP and MRSA-induced hyperpermeability was significantly attenuated by TLVP. Subsequent protein and gene expression assays determined that the V2R-induced increase in permeability is mediated by phospholipase C beta (PLCß) and the potent permeability factor angiopoietin-2. In conclusion, our results indicate that the activation of the AVP-V2R axis is critical in the pathophysiology of severe microvascular hyperpermeability during Gram-positive sepsis. The use of the antagonist TLVP should be considered as adjuvant treatment for septic patients. The results from this clinically relevant animal study are highly translational to clinical practice.

Methicillin-resistant staphylococcus aureus pneumonia in older people: a diagnostic and therapeutic challenge.

Pneumonia is one of the leading causes of death in older people, with high mortality rates (> 80%). One of the bacterial pathogens causing pneumonia is Staphylococcus aureus. The unique adaptive ability of S. aureus to a broad range of antibiotics has led to the emergence of methicillin-resistant S. aureus (MRSA) strain. MRSA pneumonia remains a relatively uncommon infection in older people, but it is associated with a very high mortality rate. We report two cases of MRSA pneumonia that highlight the severe clinical presentation and virulence of MRSA infections in geriatric population. MRSA pneumonia can present with mostly an uncontrollable clinical evolution and an infaust prognosis. Therefore, clinicians should be aware of MRSA pneumonia in patients with comorbidities, recent hospitalization with antibiotic treatment, previous MRSA infections and also in patients residing in nursing homes/revalidation centers. Low prevalence of MRSA combined with a lack of highly distinctive clinical features makes accurate targeting of empirical treatment with antibiotics very difficult. Currently, monotherapy with linezolid or vancomycin remain the first choice, in adult patients with proven MRSA infection. Despite the higher age related mortality rates, there are no specific treatment guidelines for older patients.

Congenital pulmonary airway malformation (CPAM) with initial presentation in an adult: a rare presentation of a rare disease.

Congenital pulmonary airway malformation (CPAM) is a rare congenital abnormality with unknown exact aetiology or clear genetic association. It is characterised by a failure of bronchial development and localised glandular overgrowth. Typically, it is diagnosed on prenatal ultrasound, only infrequently in children, and even less commonly in adults. We present a case of a 25-year-old man, with no previous lung diseases who presented with right-sided chest pain, fever and cough suggestive of pulmonary infection. Chest imaging, including CT scan, showed a large focal cystic mass within the right lower lobe along with ground glass opacities suggestive of CPAM. He was started on intravenous antibiotics. Bronchoscopy showed a large amount of pus in the right lung and bronchoalveolar lavage confirmed the microbiological diagnosis of methicillin-resistant Staphylococcus aureus. He improved with antibiotic treatment. He was discharged with 6-week course of antibiotics and follow-up afterward.

Serious Complications from Staphylococcal aureus in Atopic Dermatitis.

Colonization with Staphylococcal aureus is markedly more frequent in individuals with atopic dermatitis (AD) than in unaffected individuals. Chronic scratching leads to worsening of an existing defect in the epidermal barrier, which can allow S. aureus invasion into the bloodstream and subsequent systemic infections. We report two unusual cases of systemic illness in individuals with AD. One developed infective endocarditis followed by a stroke and the other developed septic arthritis and osteomyelitis. We performed an extensive literature review of reported systemic complications caused by S. aureus in patients with AD. Although reports are rare, practitioners should be aware of these important, albeit unlikely, complications of staphylococcal superinfections in individuals with AD.

Predictors of Clinical Success in the Treatment of Patients with Methicillin-Resistant Staphylococcus aureus (MRSA) Nosocomial Pneumonia (NP).

Methicillin-resistant Staphylococcus aureus (MRSA) remains an important pathogen in nosocomial pneumonia and is associated with significant morbidity and mortality. Clinical outcomes for nosocomial pneumonia are dependent on patient age, co-morbidities, severity of illness and appropriate antibiotic therapy. The objective of this secondary analysis was to identify baseline clinical variables that are associated with clinical success at the end of the study observation period. Data from a randomized blinded trial (NCT00084266) comparing linezolid (600-mg twice daily) to vancomycin (15-mg/kg twice daily, dose-adjusted) for the treatment of culture-proven MRSA pneumonia were analyzed to evaluate baseline clinical and demographic factors that may predict clinical success at end of study (EOS) (7-30 days after end of treatment). A multivariate logistic regression was conducted to identify baseline factors that are associated with clinical success. Patients treated with linezolid (OR 1.55 95% CI: 1.013, 2.355), no vasopressor receipt (OR 2.30, 95% CI: 1.303, 4.069), unilateral involvement (OR 1.70, 95% CI: 1.078, 2.681) and normal renal function (eGFR 30-80 vs >80 OR 0.48, 95% CI: 0.303, 0.750) were more likely to have clinical success. From a clinical standpoint, identifying reliable predictors of outcome and who might benefit more from one therapy versus another can help inform treatment decisions.

Hypothalamic-pituitary-adrenal axis in lethal canine Staphylococcus aureus pneumonia.

The clinical significance and even existence of critical illness-related corticosteroid insufficiency is controversial. Here, hypothalamic-pituitary-adrenal (HPA) function was characterized in severe canine Staphylococcus aureus pneumonia. Animals received antibiotics and titrated life-supportive measures. Treatment with dexamethasone, a glucocorticoid, but not desoxycorticosterone, a mineralocorticoid, improves outcome in this model. Total and free cortisol, adrenocorticotropic hormone (ACTH). and aldosterone levels, as well as responses to exogenous ACTH were measured serially. At 10 h after the onset of infection, the acute HPA axis stress response, as measured by cortisol levels, exceeded that seen with high-dose ACTH stimulation but was not predictive of outcome. In contrast to cortisol, aldosterone was largely autonomous from HPA axis control, elevated longer, and more closely associated with survival in early septic shock. Importantly, dexamethasone suppressed cortisol and ACTH levels and restored ACTH responsiveness in survivors. Differing strikingly, nonsurvivors, sepsis-induced hypercortisolemia, and high ACTH levels as well as ACTH hyporesponsiveness were not influenced by dexamethasone. During septic shock, only serial measurements and provocative testing over a well-defined timeline were able to demonstrate a strong relationship between HPA axis function and prognosis. HPA axis unresponsiveness and high aldosterone levels identify a septic shock subpopulation with poor outcomes that may have the greatest potential to benefit from new therapies.

Predictors of the pathogenicity of methicillin-resistant Staphylococcus aureus nosocomial pneumonia.

BACKGROUND AND OBJECTIVE: The clinical characteristics of patients with nosocomial pneumonia (NP) associated with methicillin-resistant Staphylococcus aureus (MRSA) infection are not well characterized. METHODS: Three hundred and thirty-seven consecutive patients with MRSA isolation from respiratory specimens who attended our hospital between April 2007 and March 2011 were enrolled. Patients characteristics diagnosed with 'true' MRSA-NP were described with regards to clinical, microbiological features, radiological features and genetic characteristics of the isolates. The diagnosis of 'true' MRSA-NP was confirmed by anti-MRSA treatment effects, Gram-staining or bronchoalveolar lavage fluid culture. RESULTS: Thirty-six patients were diagnosed with 'true' MRSA-NP, whereas 34 were diagnosed with NP with MRSA colonization. Patients with a MRSA-NP had a Pneumonia Patient Outcomes Research Team score of 5 (58.3% vs 23.5%), single cultivation of MRSA (83.3% vs 38.2%), MRSA quantitative cultivation yielding more than 10(6) CFU/mL (80.6% vs 47.1%), radiological findings other than lobar pneumonia (66.7% vs 26.5%), and a history of head, neck, oesophageal or stomach surgery (30.6% vs 11.8%). These factors were shown to be independent predictors of the pathogenicity of 'true' MRSA-NP by multivariate analysis (P < 0.05). CONCLUSIONS: 'True' MRSA-NP shows distinct clinical and radiological features from NP with MRSA colonization.

Severe hospital acquired pneumonia and septicemia due TO methicillin resistant Staphylococcus lugdunensis in a newborn in Northwestern Ethiopia.

Staphylococcus lugdunensis can cause virulent infections in immunosuppressed individuals. This report describes the first known case of hospital acquired pneumonia and septicemia due to methicillin-resistant Staphylococcus lugdunensis in a newborn at Felege Hiwot Referral Hospital, North Western Ethiopia. The strain was simultaneously resistant to trimethoprim-sulfamethoxazole, tetracycline (30 ug), chloramphenicol (30 ug), gentamycin (10ug) and ciprofloxacin (5ug) but sensitive to erythromycin (15ug) and clindamycin (10ug).

Staphylococcus aureus in early cystic fibrosis lung disease.

Staphylococcus aureus: is a common bacterial organism infecting children with cystic fibrosis (CF). Emerging evidence suggests early lower airway infection with this organism in young children with CF results in the deterioration of lung function, poorer nutrition parameters and heightens the airway inflammatory response. Despite contributing significantly to the burden of early lung disease among this group, there are ongoing controversies in the management of S. aureus infection, and gaps in our understanding of exactly how this organism causes lung disease. To reduce the morbidity and mortality of early infection ongoing research is needed to: (i) understand the early host immune response that enables this pathogen to reside within the CF lung; (ii) determine if there are organism specific factors that are associated with CF lung disease; and (iii) clarify the utility of anti-staphylococcal antibiotic prophylaxis and/or eradication in the treatment of this patient population.

Mortality increases after massive exchange transfusion with older stored blood in canines with experimental pneumonia.

Two-year-old purpose-bred beagles (n = 24) infected with Staphylococcus aureus pneumonia were randomized in a blinded fashion for exchange transfusion with either 7- or 42-day-old canine universal donor blood (80 mL/kg in 4 divided doses). Older blood increased mortality (P = .0005), the arterial alveolar oxygen gradient (24-48 hours after infection; P ≤ .01), systemic and pulmonary pressures during transfusion (4-16 hours) and pulmonary pressures for ~ 10 hours afterward (all P ≤ .02). Further, older blood caused more severe lung damage, evidenced by increased necrosis, hemorrhage, and thrombosis (P = .03) noted at the infection site postmortem. Plasma cell­free hemoglobin and nitric oxide (NO) consumption capability were elevated and haptoglobin levels were decreased with older blood during and for 32 hours after transfusion (all P ≤ .03). The low haptoglobin (r = 0.61; P = .003) and high NO consumption levels at 24 hours (r = −0.76; P < .0001) were associated with poor survival. Plasma nontransferrin-bound and labile iron were significantly elevated only during transfusion (both P = .03) and not associated with survival (P = NS). These data from canines indicate that older blood after transfusion has a propensity to hemolyze in vivo, releases vasoconstrictive cell-free hemoglobin over days, worsens pulmonary hypertension, gas exchange, and ischemic vascular damage in the infected lung, and thereby increases the risk of death from transfusion.

PEGylated liposomal vancomycin: a glimmer of hope for improving treatment outcomes in MRSA pneumonia.

Methicillin-resistant Staphylococcus aureus (MRSA) plays a significant role in the pandemic of multidrug resistant bacterial infections and is a major cause of hospital-acquired pneumonia. MRSA pneumonia carries a high morbidity and mortality rate especially in elderly diabetics with chronic kidney disease. S. aureus is highly virulent and successful respiratory pathogen. Vancomycin and linezolid are the only two antimicrobial agents FDA-approved to treat MRSA pneumonia. Standard vancomycin dosing is associated with high clinical failure rates and higher dosages are associated with increased nephrotoxicity. Pharmacokinetic and pharmacodynamic limitations are major contributors to poor outcomes with vancomycin. New agents are needed to improve treatment outcomes with MRSA pneumonia. Recently released antimicrobials with in vitro activity are not FDA-approved for treating MRSA pneumonia. Other novel agents are being investigated though none are in late-stage development. Pharmaceutical industry perception of low returns on investment, a Sisyphean regulatory environment, and obstacles to patentability have contributed to declining interest in both the development of novel antibiotics and the improvement of existing generic formulations. Despite decades of investigation into liposomal encapsulation as a drug delivery system that would increase efficacy and decrease toxicity, only liposomal amphotericin B and doxorubicin are commercially available. In this article, the pharmacokinetics and biodistribution of a novel PEGylated liposomal vancomycin formulation along with passive targeting and the enhanced permeability and retention effect of liposomal drug delivery; the pathogenesis of MRSA pneumonia; and recent patents of novel anti-MRSA agents, including inhalational liposomal vancomycin, are reviewed.

The impact of tacrolimus on the immunopathogenesis of staphylococcal enterotoxin-induced systemic inflammatory response syndrome and pneumonia.

Staphylococcal superantigens (SAg) are a family of potent exotoxins produced by Staphylococcus aureus. They play an important role in the pathogenesis of staphylococcal shock and pneumonia by causing a robust activation of the immune system and eliciting a strong surge in systemic cytokine and chemokine levels. Given the biological functions of SAg, we evaluated the efficacy of tacrolimus, a potent immunosuppressive agent, in the prophylaxis and therapy of staphylococcal TSS and pneumonia using human leukocyte antigen (HLA)-DR3 transgenic mice. Tacrolimus significantly inhibited staphylococcal SAg induced T cell activation in vitro. In vivo, tacrolimus significantly suppressed the SAg-induced elevation in serum cytokine and chemokine levels when given prophylactically, when administered immediately or even 2 h following systemic SAg challenge. Paradoxically, neither the prophylactic nor post-exposure treatment with tacrolimus protected mice from lethal SAg-induced TSS. A closer examination revealed that tacrolimus failed to suppress SAg-induced T cell proliferation and systemic pathology, including gut dysfunction. Tacrolimus also failed to protect from lethal pneumonia induced by a SAg-producing S. aureus strain. Thus, our study showed that even though T cell activation by SAg plays a major role in the immunopathogenesis of TSS and pneumonia, tacrolimus alone has no beneficial effect.

Hyper-IgE syndrome with STAT3 mutation: a case report in Mainland China.

Hyper-immunoglobulin E syndromes (HIES) including compound primary immunodeficiency and nonimmunological abnormalities are characterized by extremely high serum IgE levels, eosinophilia, eczema, susceptibility to infections, distinctive facial appearance, retention of deciduous teeth, cyst-forming pneumonias, and skeletal abnormalities. Itis reported that some cases of familial HIES are relative to autosomal dominant or recessive inheritance, but most cases are sporadic, and result from mutations in the human signal transducer and activator of transcription 3 (STAT3) gene. In this paper, we firstly report a young man diagnosed of Hyper-IgE syndrome with STAT3 mutation in Mainland China, and investigate the autosomal dominant trait of his family members.

A postinfluenza model of Staphylococcus aureus pneumonia.

BACKGROUND: Postinfluenza Staphylococcus aureus pneumonias are increasingly recognized as a major form of life-threatening infections. METHODS: A mouse model of postinfluenza S. aureus pneumonia was developed. Mice were intranasally infected with bacteria alone or bacteria plus virus. Infection was assessed by mouse survival, lung histopathology, bacterial density in the lungs, and cellular response to infection. RESULTS: Mice infected with both influenza virus and S. aureus showed higher mortality, greater lung parenchymal damage, and greater bacterial density at metastatic tissue sites than mice infected with only S. aureus. At 4 h, more polymorphonuclear leukocytes and fewer CD11c(+) cells were found in lung samples from mice infected with virus and bacteria than in those from mice infected with bacteria. alpha-Hemolysin and protein A were maximally expressed 4 h after infection, and Panton-Valentine leukocidin was maximally expressed 72 h after infection, with higher levels of alpha-hemolysin expression in mice infected with bacteria alone. Interferon gamma expression was higher in tissue collected from mice infected with virus plus bacteria than in those from bacteria-infected mice. CONCLUSIONS: The results from this model demonstrate diverse effects caused by antecedent influenza virus infection, which have a profound influence on the morbidity and mortality associated with S. aureus pneumonia.

Emergence of community-acquired meticillin-resistant Staphylococcus aureus strain USA300 as a cause of necrotising community-onset pneumonia.

Meticillin-resistant Staphylococcus aureus (MRSA), usually known as a nosocomial pathogen, has emerged as the predominant cause of skin and soft-tissue infections in many communities. Concurrent with the emergence of community-acquired MRSA (CA-MRSA), there have been increasing numbers of reports of community-acquired necrotising pneumonia in young patients and others without the classic health-care-associated risk factors. Community-onset necrotising pneumonia due to CA-MRSA is now recognised as an emerging clinical entity with distinctive clinical features and substantial morbidity and mortality. A viral prodrome (eg, influenza or influenza-like illness) followed by acute onset of shortness of breath, sepsis, and haemoptysis is the most frequent clinical presentation. The best treatment of this partly toxin-mediated disease has not been clearly defined. Whereas cases of CA-MRSA pneumonia have now been reported from almost every continent, the overall burden of disease of this emerging syndrome remains incompletely described. We report two related cases of community-onset pneumonia due to the MRSA USA300 genotype and review the literature regarding the emergence of CA-MRSA pneumonia.

Comparison of virulence in community-associated methicillin-resistant Staphylococcus aureus pulsotypes USA300 and USA400 in a rat model of pneumonia.

BACKGROUND: The predominant genetic background of community-associated methicillin-resistant Staphylococcus aureus has transitioned from USA400 to USA300 in most US communities. The explanation for this shift is unclear. We hypothesized that USA300 must be more pathogenic--specifically, that USA300 would have increased virulence when compared with USA400 in an animal model. METHODS: Rats were inoculated intratracheally with 1 of 6 S. aureus isolates from the USA300 and USA400 backgrounds. We assessed mortality, in vivo bacterial growth, and histopathology. We assessed the in vitro expression of capsule and of selected genes believed to be important in virulence in S. aureus, including agr, saeRS, sarA, alpha-toxin (hla), and Panton-Valentine leukocidin (pvl). RESULTS: USA300 isolates were more lethal, produced more severe pneumonia, and had higher in vivo bacterial density in the lung than did USA400 isolates. In vitro expression of agr, saeRS, sarA, hla, and pvl were greater in USA300 isolates. USA300 isolates were unencapsulated, whereas 2 of 3 USA400 isolates produced capsule. CONCLUSIONS: USA300 isolates were more virulent than USA400 isolates in a model of necrotizing pneumonia. The explanation for this is unclear, but it likely results from increased expression of S. aureus regulatory systems (e.g., agr, saeRS, and sarA) and the resultant upregulation of key virulence factors including alpha-toxin and PVL.

A canine model of septic shock: balancing animal welfare and scientific relevance.

A shock canine pneumonia model that permitted relief of discomfort with the use of objective criteria was developed and validated. After intrabronchial Staphylococcus aureus challenge, mechanical ventilation, antibiotics, fluids, vasopressors, sedatives, and analgesics were titrated based on algorithms for 96 h. Increasing S. aureus (1 to 8 x 10(9) colony-forming units/kg) produced decreasing survival rates (P = 0.04). From 4 to 96 h, changes in arterial-alveolar oxygen gradients, mean pulmonary artery pressure, IL-1, serum sodium levels, mechanical ventilation, and vasopressor support were ordered based on survival time [acute nonsurvivors (< or =24 h until death, n = 8) > or = subacute nonsurvivors (>24 to 96 h until death, n = 8) > or = survivors (> or =96 h until death, n = 22) (all P < 0.05)]. In the first 12 h, increases in lactate and renal abnormalities were greatest in acute nonsurvivors (all P < 0.05). Compared with survivors, subacute nonsurvivors had greater rises in cytokines and liver enzymes and greater falls in platelets, white cell counts, pH, and urine output from 24 to 96 h (all P < 0.05). Importantly, these changes were not attributable to dosages of sedation, which decreased in nonsurvivors [survivors vs. nonsurvivors: 5.0 +/- 1.0 vs. 3.8 +/- 0.7 ml x h(-1) x (fentanyl/midazolam/ medetomidine)(-1); P = 0.02]. In this model, the pain control regimen did not mask changes in metabolic function and lung injury or the need for more hemodynamic and pulmonary support related to increasing severity of sepsis. The integration into this model of both specific and supportive titrated therapies routinely used in septic patients may provide a more realistic setting to evaluate therapies for sepsis.