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The effectiveness and safety of aztreonam lysine for inhalation (AZLI) in patients with cystic fibrosis (CF) on maintenance treatment for Pseudomonas aeruginosa (PA) airway infection was evaluated in this randomized, double-blind, placebo-controlled study. To evaluate the safety and efficacy of inhaled aztreonam lysine in controlling PA infection in patients with CF. After randomization and a 28-day course of tobramycin inhalation solution (TIS), patients (n = 211; > or =6 yr; > or =3 TIS courses within previous year; FEV(1) > or = 25% and < or =75% predicted values) were treated with 75 mg AZLI or placebo, twice or three times daily for 28 days, then monitored for 56 days. The primary efficacy endpoint was time to need for additional inhaled or intravenous antipseudomonal antibiotics. Secondary endpoints included changes in respiratory symptoms (CF Questionnaire-Revised [CFQ-R] Respiratory Scale), pulmonary function (FEV(1)), and sputum PA density. Adverse events and minimum inhibitory concentrations of aztreonam for PA were monitored. AZLI treatment increased median time to need for additional antipseudomonal antibiotics for symptoms of pulmonary exacerbation by 21 days, compared with placebo (AZLI, 92 d; placebo, 71 d; P = 0.007). AZLI improved mean CFQ-R respiratory scores (5.01 points, P = 0.02), FEV(1) (6.3%, P = 0.001), and sputum PA density (-0.66 log(10) cfu/g, P = 0.006) compared with placebo; no AZLI dose-response was observed. Adverse events reported for AZLI and placebo were comparable and consistent with CF lung disease. Susceptibility of PA to aztreonam at baseline and end of therapy were similar. AZLI was effective in patients with CF using frequent TIS therapy. AZLI delayed time to need for inhaled or intravenous antipseudomonal antibiotics, improved respiratory symptoms and pulmonary function, and was well tolerated. Clinical trial registered with www.clinicaltrials.gov (NCT 00104520).

The recent entry of multiple vaccines targeting Neisseria gonorrhoeae (Ng) into the clinical development pathway has highlighted the need to establish methods of adequately assessing anti-gonococcal immune responses. Serum bactericidal activity (SBA) is utilized as a measurement of efficacy in licensure of meningococcal vaccines, but the importance of functional antibodies in preventing and/or clearing gonococcal infections remains largely unknown. In an effort to elucidate the utility of SBA as an immune correlate of protection, we sought to develop a standardized high-throughput human complement SBA (hSBA) assay for which any strain of interest could be tested under uniform conditions, with minimal screening of complement required. Utilization of IgG/IgM-depleted pooled human complement serum permitted testing of diverse serum resistant and sensitive gonococcal and unencapsulated meningococcal strains when bacteria were cultured to induce lipooligosaccharide sialylation; only one of nine randomly selected lots demonstrated intrinsic toxicity. The hSBA assay was well suited for use with multiple test serum sources, including rabbit, mouse, and human serum samples, suggesting widespread applicability.

Sutezolid (PNU-100480) is a linezolid analog with superior bactericidal activity against Mycobacterium tuberculosis in the hollow fiber, whole blood and mouse models. Like linezolid, it is unaffected by mutations conferring resistance to standard TB drugs. This study of sutezolid is its first in tuberculosis patients. Sputum smear positive tuberculosis patients were randomly assigned to sutezolid 600 mg BID (N = 25) or 1200 mg QD (N = 25), or standard 4-drug therapy (N = 9) for the first 14 days of treatment. Effects on mycobacterial burden in sputum (early bactericidal activity or EBA) were monitored as colony counts on agar and time to positivity in automated liquid culture. Bactericidal activity was also measured in ex vivo whole blood cultures (whole blood bactericidal activity or WBA) inoculated with M. tuberculosis H37Rv. All patients completed assigned treatments and began subsequent standard TB treatment according to protocol. The 90% confidence intervals (CI) for bactericidal activity in sputum over the 14 day interval excluded zero for all treatments and both monitoring methods, as did those for cumulative WBA. There were no treatment-related serious adverse events, premature discontinuations, or dose reductions due to laboratory abnormalities. There was no effect on the QT interval. Seven sutezolid-treated patients (14%) had transient, asymptomatic ALT elevations to 173±34 U/L on day 14 that subsequently normalized promptly; none met Hy's criteria for serious liver injury. The mycobactericidal activity of sutezolid 600 mg BID or 1200 mg QD was readily detected in sputum and blood. Both schedules were generally safe and well tolerated. Further studies of sutezolid in tuberculosis treatment are warranted. ClinicalTrials.gov NCT01225640.

The mechano-bactericidal activity of nanostructured surfaces has become the focus of intensive research toward the development of a new generation of antibacterial surfaces, particularly in the current era of emerging antibiotic resistance. This work demonstrates the effects of an incremental increase of nanopillar height on nanostructure-induced bacterial cell death. We propose that the mechanical lysis of bacterial cells can be influenced by the degree of elasticity and clustering of highly ordered silicon nanopillar arrays. Herein, silicon nanopillar arrays with diameter 35 nm, periodicity 90 nm and increasing heights of 220, 360, and 420 nm were fabricated using deep UV immersion lithography. Nanoarrays of 360-nm-height pillars exhibited the highest degree of bactericidal activity toward both Gram stain-negative Pseudomonas aeruginosa and Gram stain-positive Staphylococcus aureus bacteria, inducing 95 ± 5% and 83 ± 12% cell death, respectively. At heights of 360 nm, increased nanopillar elasticity contributes to the onset of pillar deformation in response to bacterial adhesion to the surface. Theoretical analyses of pillar elasticity confirm that deflection, deformation force, and mechanical energies are more significant for the substrata possessing more flexible pillars. Increased storage and release of mechanical energy may explain the enhanced bactericidal action of these nanopillar arrays toward bacterial cells contacting the surface; however, with further increase of nanopillar height (420 nm), the forces (and tensions) can be partially compensated by irreversible interpillar adhesion that reduces their bactericidal effect. These findings can be used to inform the design of next-generation mechano-responsive surfaces with tuneable bactericidal characteristics for antimicrobial surface technologies.

Klebsiella pneumoniae is a leading cause of hospital-acquired infections as well as the leading cause of neonatal sepsis worldwide. Further, increasing antibiotic resistance in this pathogen makes K. pneumoniae troublesome to treat. Despite its clinical importance, there is not yet an approved K. pneumoniae vaccine available. Here we tested antibody durability and long-term functionality of two previously reported bioconjugate vaccines targeting the K. pneumoniae capsular type K2 and O-antigen type O1v1. We demonstrate that both antibodies are durable in mice for up to six months with significant IgG titers. However, only the K2 antibodies exhibit functionality out to six months as evidenced by serum bactericidal activity and survival in a murine bacteremia challenge model. These results are another promising step towards demonstrating the clinical capacity of bioconjugate vaccines and their induction of durable antibody responses.

The currently recommended rifampicin dose (10 mg/kg) for treating tuberculosis is suboptimal. The PanACEA HIGHRIF1 trial evaluated the pharmacokinetics and early bactericidal activity of rifampicin doses of up to 40 mg/kg. Conventional statistical analyses revealed no significant exposure-response relationship. Our objectives were to explore the exposure-response relationship for high-dose rifampicin by using pharmacokinetic-pharmacodynamic modeling and to predict the early bactericidal activity of 50 mg/kg rifampicin. Data included time to Mycobacterium tuberculosis positivity of liquid cultures of sputum specimens from 83 patients with tuberculosis who were treated with 10 mg/kg rifampicin (n = 8; reference arm) or 20, 25, 30, 35, or 40 mg/kg rifampicin (n = 15/arm) for 7 days. We used a semimechanistic time-to-event approach to model the time-to-positivity data. Rifampicin exposure and baseline time to culture positivity were explored as covariates. The baseline time to culture positivity was a significant covariate on the predicted initial bacterial load, and rifampicin exposure was a significant covariate on the bacterial kill rate in sputum resulting in increased early bactericidal activity. The 90% prediction interval for the predicted median day 7 increase in time to positivity for 50 mg/kg rifampicin was 7.25-10.3 days. A significant exposure-response relationship was found between rifampicin exposure and early bactericidal activity. Clinical trial simulations showed greater early bactericidal activity for 50 mg/kg rifampicin. NCT01392911.

The discovery of vaccine antigens through whole genome sequencing (WGS) contrasts with the classical hypothesis-driven laboratory-based analysis of microbes to identify components to elicit protective immunity. This radical change in scientific direction and action in vaccine research is captured in the term . The complete genome sequence of an isolate of serogroup B (MenB) was systematically analyzed to identify proteins predicted to be secreted or exported to the outer membrane. This identified hundreds of genes coding for potential surface-exposed antigens. These were amplified, cloned in expression vectors and used to immunize mice. Antisera against 350 recombinant antigens were obtained and analyzed in a panel of immunological assays from which 28 were selected as potentially protective based on the -antibody dependent, complement mediated- serum bactericidal activity assay. Testing of these candidate vaccine antigens, using a large globally representative strain collection of Neisseria species isolated from cases of disease and carriage, indicated that no single component would be sufficient to induce broad coverage and that a \"universal\" vaccine should contain multiple antigens. The final choice of antigens to be included was based on cross-protective ability, assayed by serum bactericidal activity and maximum coverage of the extensive antigenic variability of MenB strains. The resulting multivalent vaccine formulation selected consisted of three recombinant antigens (Neisserial Heparin Binding Antigen or NHBA, Factor H binding protein or fHbp and Neisseria Adhesin A or NadA). To improve immunogenicity and potential strain coverage, an outer membrane vesicle component obtained from the epidemic New Zealand strain (OMVNz) was added to the formulation to create a four component vaccine, called 4CMenB. A series of phase 2 and 3 clinical trials were conducted to evaluate safety and tolerability and to estimate the vaccine effectiveness of human immune responses at different ages and how these were affected by various factors including concomitant vaccine use and lot-to-lot consistency. 4CMenB was approved in Europe in 2013 and introduced in the National Immunization Program in the UK starting from September 2015 when the vaccine was offered to all newborns using a 2, 4, and 12 months schedule., The effectiveness against invasive MenB disease measured at 11 months after the study start and 5 months after the second vaccination was 83% and there have been no safety concerns.

Outer membrane vesicles (OMVs) of in the group B-directed vaccine MenB-4C (Bexsero ) protect against infections with . The immunological basis for protection remains unclear. OMV vaccines generate human antibodies to and lipooligosaccharide (LOS/endotoxin), but the structural specificity of these LOS antibodies is not defined. Ten paired human sera obtained pre- and post-MenB-4C immunization were used in Western blots to probe and LOS. Post-MenB-4C sera (7v5, 19v5, and 17v5), representing individual human variability in LOS recognition, were then used to interrogate structurally defined LOSs of and strains and mutants and studied in bactericidal assays. Post-MenB-4C sera recognized both and LOS species, ~10% of total IgG to gonococcal OMV antigens. and LOSs were broadly recognized by post-IgG antibodies, but with individual variability for LOS structures. Deep truncation of LOS, specifically a K mutant without -, -, or -chain glycosylation, eliminated LOS recognition by all post-vaccine sera. Serum 7v5 IgG antibodies recognized the unsialyated L1 -chain, and a 3-PEA-HepII or 6-PEA-HepII was part of the conformational epitope. Replacing the 3-PEA on HepII with a 3-Glc blocked 7v5 IgG antibody recognition of and LOSs. Serum 19v5 recognized lactoneotetrose (LNT) or L1 LOS-expressing or with a minimal -chain structure of Gal-Glc-HepI (L8), a 3-PEA-HepII or 6-PEA-HepII was again part of the conformational epitope and a 3-Glc-HepII blocked 19v5 antibody binding. Serum 17v5 LOS antibodies recognized LNT or L1 -chains with a minimal HepI structure of three sugars and no requirement for HepII modifications. These LOS antibodies contributed to the serum bactericidal activity against . The MenB-4C vaccination elicits bactericidal IgG antibodies to conformational epitopes involving HepI and HepII glycosylated LOS structures shared between and LOS structures should be considered in next-generation gonococcal vaccine design.

•The accepted correlate of protection for meningococcal infection is the SBA assay.•Complement is key for protecting against meningococcal disease.•Selecting complement lacking strain specific antibodies is criticial for SBA assay.•Complement for serogroups A, B, C, W, and Y assays is from humans or rabbits.•rSBA is not used for serogroup B vaccine licensure due to anti-B PS IgM antibodies.•Meningococci have proteins, for example fHbp, that bind human but not other species.•Complement lacking human fH measures higher titres: the bacteria are more susceptible. Complement is an essential component of the immune system and human pathogenic organisms have developed various mechanisms for evading complement mediated serum killing. The “gold standard” for measuring the ability of vaccine-induced antibody to kill Neisseria meningitidis is the serum bactericidal antibody (SBA) assay which measures complement mediated killing via antibody. This assay requires active complement, either intrinsic from the serum being tested or the addition of exogenous complement, either from a human or from another species such as rabbit. For serogroup C, an SBA titre of ≥4 was established as the correlate of protection when using human complement and ≥8 as the threshold when using rabbit complement, based on comparative assay results. Licensure of meningococcal vaccines, including polysaccharide protein conjugate vaccines and serogroup B vaccines has been based on the immune responses measured with the SBA assay, thus on a surrogate of vaccine efficacy. This review examines the use of complement and the SBA assay to assess immunity to meningococcal infection, and provides examples of vaccine trials in different age groups where various assays have been used.

Neisseria gonorrhoeae has a significant impact on reproductive health with an estimated 82 million new cases of infection per year worldwide. Due to the ongoing emergence of multidrug-resistant N. gonorrhoeae strains, the high number of asymptomatic cases, and the risk of disease sequelae, the development of a gonococcal vaccine is urgently needed. We have previously described two potential gonococcal vaccine antigens, cNHBA (C-terminal fragment of the Neisseria Heparin Binding Antigen) and MetQ (methionine-binding protein). This study aimed to optimise these antigens for improved immune responses and to facilitate vaccine production, by investigating cNHBA fusions with the full-length MetQ protein or N-terminal and C-terminal MetQ fragments (Met1 and Met2, respectively) adjuvanted with aluminium hydroxide. The cNHBA and MetQ fragments and fusion antigens were all immunogenic in mice, generating a predominantly IgG1 response. Antibodies mediated bacterial killing via both serum bactericidal activity (SBA) and opsonophagocytic activity (OPA), and reduced adherence to cervical and urethral epithelial cells. Among the antigen fusions tested, MetQ-cNHBA and cNHBA-Met2 generated the highest SBA, OPA and adherence blocking titres and are proposed as promising optimised antigens for N. gonorrhoeae vaccine development.