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In 1997, an international surveillance program, SENTRY Antimicrobial Surveillance Program, was initiated with the aim of tracking the emergence of antimicrobial resistance worldwide. Results from reference antimicrobial susceptibility testing of bacterial pathogens (from bloodstream, inpatient and outpatient lower respiratory tract, urinary tract, and skin and soft-tissue infections) were included in an extensive database used to define antimicrobial resistance patterns throughout the world. On the basis of 1997–1999 test results from the Americas, fluoroquinolones continue to demonstrate potent in vitro activity against Enterobacteriaceae and important pathogens (Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae, and atypicals) that cause community-acquired respiratory tract infections. At published breakpoint concentrations, gatifloxacin, levofloxacin, sparfloxacin, grepafloxacin, trovafloxacin, and ciprofloxacin inhibited ∼100% of H. influenzae isolates, including those that demonstrated resistance to β-lactams and macrolides. Fluoroquinolones were also active against numerous other gram-negative bacilli and demonstrated high activity against S. pneumoniae and β-hemolytic or viridans group streptococci. New fluoroquinolones maintain activity against penicillin-resistant strains of S. pneumoniae, with a low overall resistance in this species, even among the most recent (1999) clinical isolates. The SENTRY Antimicrobial Surveillance Program will continue to monitor the antibacterial activity of these newer agents throughout the world, to identify emerging resistant strains and to facilitate possible intervention strategies as these newer compounds are used in the clinic setting.

The vaccination against bacterial respiratory diseases in calves has been generally recognised as useful for the prevention of infections. Inducing an immunological response after vaccination is important for obtaining protection from infections. The aim of the study was to investigate the effects of probiotics on the immunological response to vaccination against bacterial respiratory diseases in young Japanese Black calves. Twenty-four Japanese Black calves were randomly divided into two groups (12 calves for the research group and 12 calves for the control group) on the seventh day of life (dol). The research group received 30 g per day of live bacteria mix consisting of and until the 63 dol. The control group did not receive the bacteria mix. All calves were vaccinated against bacterial respiratory diseases twice, at 21 and 42 dol. Blood samples were obtained from all calves at 7, 21, 42 (prior to the second vaccination), 45, 49 and 63 dol for determination of antibody titres, leukocyte numbers and cytokine genes. Lymphocyte counts, T cell (CD3 , CD4 and CD8 cell) counts and relative expressions of cytokine genes (interleukin (IL)-4 and IL-17A) at 45, 49 and 63 dol were significantly higher in the research group compared than in the control group. The addition of probiotics to young Japanese Black calves' feed promoted an immunological reaction to vaccination against bacterial respiratory diseases.

Legionnaires' disease is an important cause of community-acquired and hospital-acquired pneumonia. Although uncommon, Legionnaires' disease continues to cause disease outbreaks of public health significance. The disease is caused by any species of the Gram-negative aerobic bacteria belonging to the genus Legionella; Legionella pneumophila serogroup 1 is the causative agent of most cases in Europe. In this Review we outline the global epidemiology of Legionnaires' disease, summarise its diagnosis and management, and identify research gaps and priorities. Early clinical diagnosis and prompt initiation of appropriate antibiotics for Legionella spp in all patients with community-acquired or hospital-acquired pneumonias is a crucial measure for management of the disease. Progress in typing and sequencing technologies might additionally contribute to understanding the distribution and natural history of Legionnaires' disease, and inform outbreak investigations. Control of Legionnaires' disease outbreaks relies on rapid ascertainment of descriptive epidemiological data, combined with microbiological information to identify the source and implement control measures. Further research is required to define the actual burden of disease, factors that influence susceptibility, key sources of infection, and differences in virulence between strains of Legionella species. Other requirements are improved, specific, sensitive, and rapid diagnostic tests to accurately inform management of Legionnaires' disease, and controlled clinical trials to ascertain the optimum antibiotics for treatment.

Non-typeable Haemophilus influenzae (NTHi) is a major cause of mucosal infections such as otitis media, sinusitis, conjunctivitis, and exacerbations of chronic obstructive pulmonary disease. In some regions, a strong causal relation links this pathogen with infections of the lower respiratory tract. In the past 20 years, a steady but constant increase has occurred in invasive NTHi worldwide, with perinatal infants, young children, and elderly people most at risk. Individuals with underlying comorbidities are most susceptible and infection is associated with high mortality. β-lactamase production is the predominant mechanism of resistance. However, the emergence and spread of β-lactamase-negative ampicillin-resistant strains in many regions of the world is of substantial concern, potentially necessitating changes to antibiotic treatment guidelines for community-acquired infections of the upper and lower respiratory tract and potentially increasing morbidity associated with invasive NTHi infections. Standardised surveillance protocols and typing methodologies to monitor this emerging pathogen should be implemented. International scientific organisations need to raise the profile of NTHi and to document the pathobiology of this microbe.

Klebsiella pneumoniae carbapenemases (KPCs) were originally identified in the USA in 1996. Since then, these versatile β-lactamases have spread internationally among Gram-negative bacteria, especially K pneumoniae, although their precise epidemiology is diverse across countries and regions. The mortality described among patients infected with organisms positive for KPC is high, perhaps as a result of the limited antibiotic options remaining (often colistin, tigecycline, or aminoglycosides). Triple drug combinations using colistin, tigecycline, and imipenem have recently been associated with improved survival among patients with bacteraemia. In this Review, we summarise the epidemiology of KPCs across continents, and discuss issues around detection, present antibiotic options and those in development, treatment outcome and mortality, and infection control. In view of the limitations of present treatments and the paucity of new drugs in the pipeline, infection control must be our primary defence for now.

The medical community relies on clinical expertise and published guidelines to assist physicians with choices in empirical therapy for system-based infectious syndromes, such as community-acquired pneumonia and urinary-tract infections (UTIs). From the late 1990s, multidrug-resistant Enterobacteriaceae (mostly Escherichia coli) that produce extended-spectrum β lactamases (ESBLs), such as the CTX-M enzymes, have emerged within the community setting as an important cause of UTIs. Recent reports have also described ESBL-producing E coli as a cause of bloodstream infections associated with these community-onset UTIs. The carbapenems are widely regarded as the drugs of choice for the treatment of severe infections caused by ESBL-producing Enterobacteriaceae, although comparative clinical trials are scarce. Thus, more rapid diagnostic testing of ESBL-producing bacteria and the possible modification of guidelines for community-onset bacteraemia associated with UTIs are required.

Mesenchymal stem cells secrete paracrine factors that can regulate lung permeability and decrease inflammation, making it a potentially attractive therapy for acute lung injury. However, concerns exist whether mesenchymal stem cells' immunomodulatory properties may have detrimental effects if targeted toward infectious causes of lung injury. Therefore, we tested the effect of mesenchymal stem cells on lung fluid balance, acute inflammation, and bacterial clearance. We developed an Escherichia coli pneumonia model in our ex vivo perfused human lung to test the therapeutic effects of mesenchymal stem cells on bacterial-induced acute lung injury. Clinical-grade human mesenchymal stem cells restored alveolar fluid clearance to a normal level, decreased inflammation, and were associated with increased bacterial killing and reduced bacteremia, in part through increased alveolar macrophage phagocytosis and secretion of antimicrobial factors. Keratinocyte growth factor, a soluble factor secreted by mesenchymal stem cells, duplicated most of the antimicrobial effects. In subsequent in vitro studies, we discovered that human monocytes expressed the keratinocyte growth factor receptor, and that keratinocyte growth factor decreased apoptosis of human monocytes through AKT phosphorylation, an effect that increased bacterial clearance. Inhibition of keratinocyte growth factor by a neutralizing antibody reduced the antimicrobial effects of mesenchymal stem cells in the ex vivo perfused human lung and monocytes grown in vitro injured with E. coli bacteria. In E. coli-injured human lungs, mesenchymal stem cells restored alveolar fluid clearance, reduced inflammation, and exerted antimicrobial activity, in part through keratinocyte growth factor secretion.

Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) can be caused by a wide variety of bacteria that originate from the patient flora or the health care environment. We review the medical and microbiology literature and the results of the SENTRY Antimicrobial Surveillance Program (1997-2008) to establish the pathogens most likely to cause HABP or VABP. In all studies, a consistent 6 organisms (Staphylococcus aureus [28.0%], Pseudomonas aeruginosa [21.8%], Klebsiella species [9.8%], Escherichia coli [6.9%], Acinetobacter species [6.8%], and Enterobacter species [6.3%]) caused ∼80% of episodes, with lower prevalences of Serratia species, Stenotrophomonas maltophilia, and community-acquired pathogens, such as pneumococci and Haemophilus influenzae. Slight changes in the pathogen order were noted among geographic regions; Latin America had an increased incidence of nonfermentative gram-negative bacilli. In addition, VABP isolates of the same species had a mean of 5%-10% less susceptibility to frequently used extended-spectrum antimicrobials, and the rate of drug resistance among HABP and VABP pathogens has been increasing by 1% per year (2004-2008). In conclusion, the empirical treatment of HABP and VABP due to prevailing bacterial causes and emerging drug resistance has become more challenging and requires use of multidrug empirical treatment regimens for routine clinical practice. These facts have profound impact on the choices of comparison therapies to be applied in contemporary new drug clinical trials for pneumonia.

Lower respiratory tract infections are often treated with antibiotics without evidence of clinically relevant bacterial disease. Serum calcitonin precursor concentrations, including procalcitonin, are raised in bacterial infections. We aimed to assess a procalcitonin-based therapeutic strategy to reduce antibiotic use in lower respiratory tract infections with a new rapid and sensitive assay. 243 patients admitted with suspected lower respiratory tract infections were randomly assigned standard care (standard group; n=119) or procalcitonin-guided treatment (procalcitonin group; n=124). On the basis of serum procalcitonin concentrations, use of antibiotics was more or less discouraged (<0·1 μg/L or <0·25 μg/L) or encouraged (≥;0·5 μg/L or ≥0·25 μg/L), respectively. Reevaluation was possible after 6–24 h in both groups. Primary endpoint was use of antibiotics and analysis was by intention to treat. Final diagnoses were pneumonia (n=87; 36%), acute exacerbation of chronic obstructive pulmonary disease (60; 25%), acute bronchitis (59; 24%), asthma (13; 5%), and other respiratory affections (24; 10%). Serological evidence of viral infection was recorded in 141 of 175 tested patients (81%). Bacterial cultures were positive from sputum in 51 (21%) and from blood in 16 (7%). In the procalcitonin group, the adjusted relative risk of antibiotic exposure was 0·49 (95% CI 0·44–0·55; p<0·0001) compared with the standard group. Antibiotic use was significantly reduced in all diagnostic subgroups. Clinical and laboratory outcome was similar in both groups and favourable in 235 (97%). Procalcitonin guidance substantially reduced antibiotic use in lower respiratory tract infections. Withholding antimicrobial treatment did not compromise outcome. In view of the current overuse of antimicrobial therapy in often self-limiting acute respiratory tract infections, treatment based on procalcitonin measurement could have important clinical and financial implications. Published online Feb 10, 2004. http://image.thelancet.com/extras/04art1162web.pdf

A hallmark of pulmonary tuberculosis (TB) is the formation of granulomas. However, the immune factors that drive the formation of a protective granuloma during latent TB, and the factors that drive the formation of inflammatory granulomas during active TB, are not well defined. The objective of this study was to identify the underlying immune mechanisms involved in formation of inflammatory granulomas seen during active TB. The immune mediators involved in inflammatory granuloma formation during TB were assessed using human samples and experimental models of Mycobacterium tuberculosis infection, using molecular and immunologic techniques. We demonstrate that in human patients with active TB and in nonhuman primate models of M. tuberculosis infection, neutrophils producing S100 proteins are dominant within the inflammatory lung granulomas seen during active TB. Using the mouse model of TB, we demonstrate that the exacerbated lung inflammation seen as a result of neutrophilic accumulation is dependent on S100A8/A9 proteins. S100A8/A9 proteins promote neutrophil accumulation by inducing production of proinflammatory chemokines and cytokines, and influencing leukocyte trafficking. Importantly, serum levels of S100A8/A9 proteins along with neutrophil-associated chemokines, such as keratinocyte chemoattractant, can be used as potential surrogate biomarkers to assess lung inflammation and disease severity in human TB. Our results thus show a major pathologic role for S100A8/A9 proteins in mediating neutrophil accumulation and inflammation associated with TB. Thus, targeting specific molecules, such as S100A8/A9 proteins, has the potential to decrease lung tissue damage without impacting protective immunity against TB.