Antibiotic Susceptibility Among Aerobic Gram-negative Bacilli in Intensive Care Units in 5 European Countries

Context  Surveillance of antibiotic resistance is especially important in intensive care units (ICUs) because the infection rates are much higher there than in other hospital wards and most epidemics with multiresistant bacteria originate in ICUs. Objective  To evaluate the incidence of decreased antibiotic susceptibility among aerobic gram-negative bacilli isolated from patients in ICUs. Design  Consecutive specimens collected on clinical indications from ICU patients were cultured and tested. Minimum inhibitory concentrations for amikacin, ceftazidime, ceftriaxone, ciprofloxacin, gentamicin, imipenem, piperacillin, and piperacillin-tazobactam were determined using E test. Setting  Eighteen hospitals in Belgium, 40 in France, 20 in Portugal, 30 in Spain, and 10 in Sweden. Subjects  A total of 9166 gram-negative strains were initially isolated from 7308 patients between June 1994 and June 1995. Main Outcome Measures  The incidence of decreased susceptibility, defined as the sum of resistant and intermediate categories with use of the minimum inhibitory concentration break points recommended by the National Committee for Clinical Laboratory Standards. Results  The most frequently isolated organisms were Enterobacteriaceae (59\%) followed by Pseudomonas aeruginosa (24\%). The main sources were respiratory tract (42\%), urine (26\%), blood (14\%), abdomen (11\%), and skin and soft tissue (7\%). Decreased antibiotic susceptibility across all species and drugs was highest in Portuguese ICUs followed by French, Spanish, Belgian, and Swedish ICUs. The highest incidence of resistance was seen in all countries among P aeruginosa (up to 37\% resistant to ciprofloxacin in Portuguese ICUs and 46\% resistant to gentamicin in French ICUs), Enterobacter species, Acinetobacter species, and Stenotrophomonas maltophilia, and in Portugal and France among Klebsiella species. Conclusion  The high incidence of reduced antibiotic susceptibility among gram-negative bacteria in these ICUs suggests that more effective strategies are needed to control the selection and spread of resistant organisms.      

Role of the CXCR4/SDF-1 chemokine axis in circulating neutrophil homeostasis

The bone marrow is the primary site for neutrophil production and release into the circulation. Because the CXC chemokine receptor-4/stromal derived factor-1 (CXCR4/SDF-1) axis plays a central role in the interactions of hematopoietic stem cells, lymphocytes, and developing neutrophils in the marrow, we investigated whether reciprocal CXCR4-dependent mechanisms might be involved in neutrophil release and subsequent return to the marrow following circulation. Neutralizing antibody to CXCR4 reduced marrow retention of infused neutrophils (45.7% +/- 0.5% to 6.9% +/- 0.5%) and was found to mobilize neutrophils from marrow (34.4% +/- 4.4%). Neutrophil CXCR4 expression and SDF-1-induced calcium flux decreased with maturation and activation of the cells, corresponding to the decreased marrow homing associated with these characteristics in vivo. Infusion of the inflammatory mediator and CXCR2 ligand KC led to mobilization of neutrophils from marrow by itself and was augmented 3-fold by low doses of CXCR4-blocking antibody that otherwise had no mobilizing effect. Examination of KC and SDF-1 calcium signaling demonstrated that the effect of KC may, in part, be due to heterologous desensitization to SDF-1. These results suggest that the CXCR4/SDF-1 axis is critical in circulating neutrophil homeostasis and that it may participate in the rapid release of neutrophils from the marrow during inflammation through a novel interaction with inflammatory CXC chemokines.     

Sjögren syndrome associated with hepatitis C virus: a multicenter analysis of 137 cases

To define the clinical and immunologic pattern of expression of Sj?gren syndrome (SS) associated with chronic hepatitis C virus (HCV) infection, we conducted a multicenter study aiming to collect a large number of patients with SS and HCV infection. Inclusion criteria were the fulfillment of at least 4 of the classification criteria for SS proposed by the European Community Study Group and repeated positive HCV serology, confirmed by recombinant immunoblot assay and/or detection of serum HCV-RNA by polymerase chain reaction. One hundred thirty-seven patients were included (104 female and 33 male; mean age, 65 yr). Seventy-nine (58%) patients presented a systemic process with diverse extraglandular manifestations, with articular involvement (44%), vasculitis (20%), and neuropathy (16%) being the most frequent features observed. The main immunologic features were antinuclear antibodies (65%), hypocomplementemia (51%), and cryoglobulinemia (50%). Cryoglobulins were associated with a higher frequency of cutaneous vasculitis, rheumatoid factor, and hypocomplementemia. Thirty-two (23%) patients had positive anti-Ro/SS-A and/or anti-La/SS-B antibodies; these patients were predominantly women and had a higher prevalence of some extraglandular features and a lower frequency of liver involvement. Nineteen (14%) patients developed neoplasia, with hematologic neoplasia (8 cases) and hepatocellular carcinoma (6 cases) being the most frequent types. Eighty-five percent of SS-HCV patients also fulfilled the recently proposed 2002 classification criteria for SS. In conclusion, HCV-associated SS is indistinguishable in most cases from the primary form using the most recent set of classification criteria. Chronic HCV infection should be considered an exclusion criterion for the classification of primary SS, not because it mimics primary SS, but because the virus may be implicated in the development of SS in a specific subset of patients. We propose the term "SS secondary to HCV" when these patients fulfill the 2002 classification criteria for SS.     

Prognostic value of telomere length in acute coronary syndrome

Telomere and telomerase are involved in cellular and organismal ageing and have been related to human diseases. Coronary artery disease is one of the most common age-related health problems in developed countries. Nevertheless, the specific role of cellular ageing in this process is still unclear. In this study, we analyze the possible prognostic value of telomere length and telomerase polymorphisms in a population of 150 middle aged males (mean age 62 ± 7) admitted for acute coronary syndrome who were followed up for more than 600 days. Peripheral blood samples were obtained and relative and comparative qPCR was used to measure telomere length and real time PCR to study the polymorphisms. Two prognostic combined events were defined. Long telomere length was revealed as an independent predictor (protector) of combined event presentation during long term follow up in our patients.     

Nocardia brasiliensis induces an immunosuppressive microenvironment that favors chronic infection in BALB/c mice

Nocardia brasiliensis is an intracellular microorganism and the most common etiologic agent of actinomycetoma in the Americas. Several intracellular pathogens induce an immunosuppressive microenvironment through increases in CD4+ Foxp3+ regulatory T cells (Treg), thus downregulating other T-cell subpopulations and assuring survival in the host. In this study, we determined whether N. brasiliensis modulates T-lymphocyte responses and their related cytokine profiles in a murine experimental model. We also examined the relationship between N. brasiliensis immunomodulation and pathogenesis and bacterial survival. In early infection, Th17/Tc17 cells were increased at day 3 (P < 0.05) in footpad tissue and spleen. Treg subpopulations peaked at days 7 and 15 (P < 0.01) in the footpad and spleen, respectively. Transforming growth factor β1 (TGF-β1) and interleuki-10 (IL-10) are cytokines known for their immunosuppressive effects. During early and chronic infections, these cytokines were elevated with increased TGF-β1 levels from days 3 to 30 (P < 0.01) and sustained IL-10 expression throughout infection compared to uninfected mice. IL-6 production was increased at day 3 (P < 0.01), whereas gamma interferon (IFN-γ), IL-17A, and IL-23 levels were highest at day 15 postinfection (P < 0.01) when a decrease in the bacterial load (>1 log) was also observed (P < 0.05). After these changes, at 30 to 60 days postinfection, IFN-γ production was decreased, whereas the expression of anti-inflammatory cytokines and the bacterial load again increased (P < 0.05). The increment in Treg cells and the related cytokine profile correlated with reduced inflammation at day 15 (P < 0.05) in the footpad. We conclude that N. brasiliensis modulates the immune system to induce an immunosuppressive microenvironment that benefits its survival during the chronic stage of infection.     

The Coordinated Action of CC Chemokines in the Lung Orchestrates Allergic Inflammation and Airway Hyperresponsiveness

The complex pathophysiology of lung allergic inflammation and bronchial hyperresponsiveness (BHR) that characterize asthma is achieved by the regulated accumulation and activation of different leukocyte subsets in the lung. The development and maintenance of these processes correlate with the coordinated production of chemokines. Here, we have assessed the role that different chemokines play in lung allergic inflammation and BHR by blocking their activities in vivo. Our results show that blockage of each one of these chemokines reduces both lung leukocyte infiltration and BHR in a substantially different way. Thus, eotaxin neutralization reduces specifically BHR and lung eosinophilia transiently after each antigen exposure. Monocyte chemoattractant protein (MCP)-5 neutralization abolishes BHR not by affecting the accumulation of inflammatory leukocytes in the airways, but rather by altering the trafficking of the eosinophils and other leukocytes through the lung interstitium. Neutralization of RANTES (regulated upon activation, normal T cell expressed and secreted) receptor(s) with a receptor antagonist decreases significantly lymphocyte and eosinophil infiltration as well as mRNA expression of eotaxin and RANTES. In contrast, neutralization of one of the ligands for RANTES receptors, macrophage-inflammatory protein 1α, reduces only slightly lung eosinophilia and BHR. Finally, MCP-1 neutralization diminishes drastically BHR and inflammation, and this correlates with a pronounced decrease in monocyte- and lymphocyte-derived inflammatory mediators. These results suggest that different chemokines activate different cellular and molecular pathways that in a coordinated fashion contribute to the complex pathophysiology of asthma, and that their individual blockage results in intervention at different levels of these processes.     

Phase II study of pegylated liposomal doxorubicin plus vinorelbine in breast cancer with previous anthracycline exposure

Thirty-five patients with metastatic breast cancer (MBC) entered a phase II study of pegylated liposomal doxorubicin 35 mg/m2 intravenously (i.v.) on day 1 plus vinorelbine 30 mg/m2 i.v. on day 1 every 4 weeks. Patients were required to have measurable disease, previous chemotherapy with an anthracycline-containing regimen, and a normal left ventricular ejection fraction (LVEF). Thirty-four patients were assessable for response and toxicity. The overall response rate (on an intent-to-treat basis) was 35% (12 of 34; 95% CI, 20%-54%). One complete response and 11 partial responses were noted. In addition, 14 patients (41%) had stable disease of > 4 months duration, and 7 patients (20.5%) had disease progression. The response rates to the combination when it was used as first- and second-line chemotherapy were 31% (4 of 13) and 38% (8 of 21), respectively. Median time to disease progression was 7 months (range, 1-35 months) and median overall survival was 13 months (range, 2 to > 62 months). Neutropenia was the most frequent toxicity (grade 4 in 44% of patients and 19% of cycles), but neutropenic fever was seen in only 3 cases. No septic deaths occurred. Nonhematologic grade 3 side effects included skin toxicity (palmar-plantar erythrodysesthesia syndrome, 6%) and mucositis (15%). Late alopecia was seen in 53% of patients (grade 1 in 41%, and grade 2 in 12%). The median LVEFs were 64% (range, 50%-81%) at baseline and 62% (range, 37%-70%) after treatment. Three patients presented an LVEF decrease to < 50%; however, no clinical heart failure was noted, and 2 of these patients recovered normal values after cessation of therapy. The combination of pegylated liposomal doxorubicin and vinorelbine can be safely administered to patients with anthracycline-pretreated MBC and is active in this population.     

Pharmacokinetic drug evaluation of vorapaxar for secondary prevention after acute coronary syndrome

Introduction: Vorapaxar is the first protease-activated receptor-1 inhibitor approved for clinical use. Its main indication is the reduction in thrombotic cardiovascular events in patients with previous myocardial infarction or symptomatic peripheral artery disease.

Areas covered: This article reviews the pharmacokinetics of vorapaxar and its potential use in secondary prevention after an acute coronary syndrome.

Expert opinion: Vorapaxar inhibits platelet aggregation mediated by thrombin. This effect is carried out without affecting to coagulation parameters and bleeding times. This drug has showed a significant reduction of cardiovascular events in patients with chronic atherosclerosis but not during the admission for an acute coronary syndrome. The rate of major bleeding found in patients treated with vorapaxar in randomized trials was consistently higher than placebo in most of the analyzed subgroups. For this reason, cautious evaluation of risk-benefit profiles should be required before prescribing this drug.