The global burden of disease caused by respiratory syncytial virus (RSV) is increasingly recognised, not only in infants, but also in older adults (aged ≥65 years). Advances in knowledge of the structural biology of the RSV surface fusion glycoprotein have revolutionised RSV vaccine development by providing a new target for preventive interventions. The RSV vaccine landscape has rapidly expanded to include 19 vaccine candidates and monoclonal antibodies (mAbs) in clinical trials, reflecting the urgency of reducing this global health problem and hence the prioritisation of RSV vaccine development. The candidates include mAbs and vaccines using four approaches: (1) particle-based, (2) live-attenuated or chimeric, (3) subunit, (4) vector-based. Late-phase RSV vaccine trial failures highlight gaps in knowledge regarding immunological protection and provide lessons for future development. In this Review, we highlight promising new approaches for RSV vaccine design and provide a comprehensive overview of RSV vaccine candidates and mAbs in clinical development to prevent one of the most common and severe infectious diseases in young children and older adults worldwide.
The first European survey of the prevalence of antibiotic resistance in Haemophilus influenzae was conducted between February and October 1986. Eighty laboratories in nine countries participated (Austria, Belgium, France, FRG, The Netherlands, Spain, Sweden, Switzerland and the UK). A total of 1,961 clinical isolates was examined for type b encapsulation, beta-lactamase production and susceptibility to ampicillin, chloramphenicol, cefaclor, erythromycin and tetracycline, using a unique microdilution method. The proportion of isolates resistant to these antibiotics varied considerably between individual countries. The highest prevalence of ampicillin resistance was found in Spain (30.6%), and the lowest in the FRG (1.6%), with a mean value of 10% for all countries. Chloramphenicol resistance was highest in Spain (24.9%) and Belgium (10.9%) and lowest in The Netherlands (0.6%) and Austria (0.5%), with a mean value of 4.7%. Resistance to erythromycin ranged from 27% of the isolates in The Netherlands to 1.1% in Austria. For tetracycline, values ranged from 1.5% in the UK to 17.8% in Belgium and 25.4% in Spain. The lowest mean prevalence of resistance was observed for cefaclor (breakpoint 8 mg/l): 5% or less in all countries. These inter-country differences could only partially be explained by variations in the proportion of type b strains, the source of the isolates and the mode of collection.
Children represent a significant proportion of the global tuberculosis (TB) burden, and may be disproportionately more affected by its most severe clinical manifestations. Currently available treatments for pediatric drug-susceptible (DS) and drug-resistant (DR) TB, albeit generally effective, are hampered by high pill burden, long duration of treatment, coexistent toxicities, and an overall lack of suitable, child-friendly formulations. The complex and burdensome nature of administering the existing regimens to treat DS TB also contributes to the rise of DR TB strains. Despite the availability and use of these therapies for decades, a dearth of dosing evidence in children underscores the importance of sustained efforts for TB drug development to better meet the treatment needs of children with TB. Several new TB drugs and regimens with promising activity against both DS and DR TB strains have recently entered clinical development and are in various phases of clinical evaluation in adults or have received marketing authorization for adults. However, initiation of clinical trials to evaluate these drugs in children is often deferred, pending the availability of complete safety and efficacy data in adults or after drug approval. This document summarizes consensus statements from an international panel of childhood TB opinion leaders which support the initiation of evaluation of new TB drugs and regimens in children at earlier phases of the TB Drug development cycle.
Four hundred and thirty-one Streptococcus pneumoniae, 1272 Haemophilus influenzae and 305 Moraxella (Branhamella) catarrhalis were isolated from sputa and identified in 28 UK laboratories during a ten week period in 1990. Disc diffusion susceptibility testing was performed in each centre using identical methods. Species-specific susceptibility breakpoints applied to data for six antimicrobial agents were determined from the distribution of isolates according to zone diameters of inhibition measured in participating laboratories and were correlated with minimum inhibitory concentration data obtained with 302 isolates sent to the coordinating centre. Inter-laboratory reproducibility was estimated by comparing peripheral and coordinating centre results for these 302 isolates and by distributing five reference strains to all laboratories for testing. Reduced susceptibility to ampicillin and amoxycillin-clavulanate was detected in less than 3% of S. pneumoniae, but 8.1% were resistant to tetracycline and 6.5% to erythromycin. Resistance to ampicillin due to production of beta-lactamase occurred in 9.4% of H. influenzae; another 5.2% were resistant to ampicillin and amoxycillin-clavulanate but were beta-lactamase-negative. 4.5% were resistant to tetracycline and most (86.6%) had MICs greater than or equal to 1 mg/L of erythromycin. Zone diameters around ampicillin discs were greater than or equal to 10 mm smaller than those around amoxycillin-clavulanate discs for 241 (79%) of M. catarrhalis. Although only 193/241 had been reported to be beta-lactamase positive by participating laboratories, data obtained at the coordinating centre confirmed that greater than or equal to 10 mm and less than or equal to 3 mm zone size differences correlated with beta-lactamase-positive and -negative isolates respectively. No M. catarrhalis were resistant to amoxycillin-clavulanate and less than 4% were resistant to either tetracycline or erythromycin. The prevalence of resistance to cefaclor was highest among H. influenzae (5.2%) and lowest among S. pneumoniae (0.9%). Only seven of 2008 isolates (two to three per species) were resistant to cefixime. The data suggest that the prevalence of resistance to ampicillin, tetracycline and erythromycin must be taken into consideration when treating respiratory infections.
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