We sequenced the genomes of 3,615 strains of serotype Emm protein 1 (M1) group A Streptococcus to unravel the nature and timing of molecular events contributing to the emergence, dissemination, and ...genetic diversification of an unusually virulent clone that now causes epidemic human infections worldwide. We discovered that the contemporary epidemic clone emerged in stepwise fashion from a precursor cell that first contained the phage encoding an extracellular DNase virulence factor (streptococcal DNase D2, SdaD2) and subsequently acquired the phage encoding the SpeA1 variant of the streptococcal pyrogenic exotoxin A superantigen. The SpeA2 toxin variant evolved from SpeA1 by a single-nucleotide change in the M1 progenitor strain before acquisition by horizontal gene transfer of a large chromosomal region encoding secreted toxins NAD ⁺-glycohydrolase and streptolysin O. Acquisition of this 36-kb region in the early 1980s into just one cell containing the phage-encoded sdaD2 and speA2 genes was the final major molecular event preceding the emergence and rapid intercontinental spread of the contemporary epidemic clone. Thus, we resolve a decades-old controversy about the type and sequence of genomic alterations that produced this explosive epidemic. Analysis of comprehensive, population-based contemporary invasive strains from seven countries identified strong patterns of temporal population structure. Compared with a preepidemic reference strain, the contemporary clone is significantly more virulent in nonhuman primate models of pharyngitis and necrotizing fasciitis. A key finding is that the molecular evolutionary events transpiring in just one bacterial cell ultimately have produced millions of human infections worldwide.
Abstract Purpose To investigate the association of potential risk factors for urinary tract infections (UTI) caused by E. coli producing ESBL vs. not producing ESBL in Iceland. Methods Observational, ...case-control study including a cohort of 27,747 patients (22,800 females, 4,947 males; 1207 cases, 26,540 controls) of all ages with UTI caused by E. coli in 2012 to 2021 at the clinical microbiology laboratory covering about 2/3 of the Icelandic population. Clinical patient data was obtained from three national databases. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) as a measure of association between ESBL and exposure variables. Results The proportion of samples with ESBL-producing E. coli increased during the study period, from 2.6% in 2012 to 7.6% in 2021 ( p < 0.001). ESBL-positive strains were detected in 1207 individuals (4.4%), 905 females (4.0%) and 302 males (6.1%). The following risk factors were identified: Male sex, higher age, institution type (hospital, nursing home), hospital-associated UTI, Charlson comorbidity index score ≥ 3, history of cystitis or hospitalization in the past year, and prescriptions for certain antibiotics or proton pump inhibitors (PPIs: OR 1.51) in the past half year. The antibiotic associated with the highest risk was ciprofloxacin (OR 2.45). Conclusion The prevalence of UTIs caused by ESBL-producing E. coli has been increasing in Iceland. The strongest risk factors for ESBL production were previous antibiotic use, especially ciprofloxacin, and previous PPI use, both considered to be overprescribed. It is important to promote the prudent use of these drugs.
The identification of the molecular events responsible for strain emergence, enhanced virulence, and epidemicity has been a long-pursued goal in infectious diseases research. A recent analysis of ...3,615 genomes of serotype M1 group A Streptococcus strains (the so-called "flesh-eating" bacterium) identified a recombination event that coincides with the global M1 pandemic beginning in the early 1980s. Here, we have shown that the allelic variation that results from this recombination event, which replaces the chromosomal region encoding secreted NADase and streptolysin O, is the key driver of increased toxin production and enhanced infection severity of the M1 pandemic strains. Using isoallelic mutant strains, we found that 3 polymorphisms in this toxin gene region increase resistance to killing by human polymorphonuclear leukocytes, increase bacterial proliferation, and increase virulence in animal models of pharyngitis and necrotizing fasciitis. Genome sequencing of an additional 1,125 streptococcal strains and virulence studies revealed that a highly similar recombinational replacement event underlies an ongoing intercontinental epidemic of serotype M89 group A Streptococcus infections. By identifying the molecular changes that enhance upper respiratory tract fitness, increased resistance to innate immunity, and increased tissue destruction, we describe a mechanism that underpins epidemic streptococcal infections, which have affected many millions of people.
Streptococcus pneumoniae is a cause of infections that range in severity from acute otitis media (AOM) to pneumonia and invasive pneumococcal disease (IPD). The 10-valent pneumococcal conjugate ...vaccine (PHiD-CV10) was introduced into the Icelandic paediatric immunisation programme in 2011. The aim was to estimate the population impact and cost-effectiveness of PHiD-CV10 introduction.
Data on primary care visits from 2005-2015 and hospitalisations from 2005-2017 were obtained from population-based registries. A Bayesian time series analysis with synthetic controls was employed to estimate the number of cases of AOM, pneumonia and IPD that would have occurred between 2013-2017, had PHiD-CV10 not been introduced. Prevented cases were calculated by subtracting the observed number of cases from this estimate. The cost of the programme was calculated accounting for cost-savings due to prevented cases.
The introduction of PHiD-CV10 prevented 13,767 (95% credible interval CI 2,511-29,410) visits for AOM from 2013-2015, and prevented 1,814 (95%CI -523-4,512) hospitalisations for pneumonia and 53 (95%CI -17-177) admissions for IPD from 2013-2017. Visits for AOM decreased both among young children and among children 4-19 years of age, with rate ratios between 0.72-0.89. Decreases were observed in both pneumonia hospitalisations (rate ratios between 0.67-0.92) and IPD (rate ratios between 0.27-0.94). The total cost of implementing PHiD-CV10 in Iceland was -7,463,176 United States Dollars (USD) (95%CI -16,159,551-582,135) with 2.1 USD (95%CI 0.2-4.7) saved for every 1 USD spent.
The introduction of PHiD-CV10 was associated with large decreases in visits and hospitalisations for infections commonly caused by pneumococcus and was cost-saving during the first five years of the immunisation programme.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Penicillin non-susceptible (PNSP) and multi-resistant pneumococci have been prevalent in Iceland since early nineties, mainly causing problems in treatment of acute otitis media. The 10-valent ...protein conjugated pneumococcal vaccine (PHiD-CV) was introduced into the childhood vaccination program in 2011. The aim of the study was to investigate the changes in antimicrobial susceptibility and serotype distribution of penicillin non-susceptible pneumococci (PNSP) in Iceland 2011-2017.
All pneumococcal isolates identified at the Landspítali University Hospital in 2011-2017, excluding isolates from the nasopharynx and throat were studied. Susceptibility testing was done according to the EUCAST guidelines using disk diffusion with chloramphenicol, erythromycin, clindamycin, tetracycline, trimethoprim/sulfamethoxazole and oxacillin for PNSP screening. Penicillin and ceftriaxone minimum inhibitory concentrations (MIC) were measured for oxacillin resistant isolates using the E-test. Serotyping was done using latex agglutination and/or multiplex PCR. The total number of pneumococcal isolates that met the study criteria was 1,706, of which 516 (30.2%) were PNSP, and declining with time. PNSP isolates of PHiD-CV vaccine serotypes (VT) were 362/516 (70.2%) declining with time, 132/143 (92.3%) in 2011 and 17/54 (31.5%) in 2017. PNSP were most commonly of serotype 19F, 317/516 isolates declining with time, 124/143 in 2011 and 15/54 in 2017. Their number decreased in all age groups, but mainly in the youngest children. PNSP isolates of non PHiD-CV vaccine serotypes (NVT) were 154/516, increasing with time, 11/14, in 2011 and 37/54 in 2017. The most common emerging NVTs in 2011 and 2017 were 6C, 1/143 and 10/54 respectively.
PNSP of VTs have virtually disappeared from children with pneumococcal diseases after the initiation of pneumococcal vaccination in Iceland and a clear herd effect was observed. This was mainly driven by a decrease of PNSP isolates belonging to a serotype 19F multi-resistant lineage. However, emerging multi-resistant NVT isolates are of concern.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A whole-population study including 58794 episodes of acute otitis media (AOM) revealed a 22% reduction in all-cause AOM in children <3 years of age after initiation of 10-valent pneumococcal ...Haemophilus influenzae protein-D conjugate vaccine (Cox regression model, repeated events).
Abstract
Background
The 10-valent pneumococcal conjugate vaccine (PHiD-CV10) was introduced in Iceland in 2011, without catch-up. The aim of this study was to estimate vaccine impact (VI) on acute otitis media (AOM).
Methods
In this whole-population study, all primary care visits due to AOM from 2005 to 2015 in children <3 years of age were included. Birth cohorts were grouped as vaccine noneligible (VNEC) or vaccine eligible (VEC). Crude incidence rates (IRs) were compared between the VNEC and VEC. A Cox regression model for repeated events was used to model the individual-level data. VI was calculated as (hazard ratio HR - 1) × 100%.
Results
Included were 53150 children, with 140912 person-years of follow-up and 58794 AOM episodes. Both IR and the mean number of episodes differed significantly between VNEC and VEC; 43 compared to 38 episodes per 100 person-years and 1.61 episodes per child compared to 1.37. IR was significantly reduced in all age brackets, with the largest reduction in children <4 months of age (40% 95% confidence interval {CI}, 31%-49%). The VI on all-cause AOM was 22% (95% CI, 12%-31%). The impact was mediated through its effect on the first (HR, 0.84 95% CI, .82-.86) and second (HR, 0.95 95% CI, .93-.98) episodes.
Conclusions
The impact of PHiD-CV10 on all-cause AOM was considerable, mediated mainly by preventing the first two episodes of AOM. A decrease in the IR of AOM in children too young to receive direct vaccine protection was demonstrated, suggesting herd effect.
Antimicrobial resistance is a growing global health threat. To preserve the effectiveness of antimicrobials, it is important to reduce demand for antimicrobials.
The objective of the study was to ...screen the existing peer-reviewed literature to identify articles that addressed the potential impact of influenza or Pneumococcus vaccination on antibiotic usage.
Data sources: PubMed, Embase
Study eligibility criteria: Clinical studies where antimicrobial prescribing was assessed in both vaccinated and unvaccinated populations.
Participants and interventions: All patient populations were included (infants, children, adults and elderly), where the effects of the intervention (vaccination) was assessed
We identified unique 3638 publications, of which 26 were judged to be of sufficiently high quality to allow the calculation of the potential impact of vaccination. Of these studies 23/26 found a significant reduction in antibiotic use by at least one of the parameters assessed.
Different measures used to define anti-microbial use, studies typically focus on specific risk groups and most studies are from high-income countries.
Conclusions and implications of key findings: Despite the limitations of the review, the evidence indicates that improved coverage with existing vaccines may significantly reduce antimicrobial demand. This suggests it may be a valuable tool for antimicrobial stewardship.
Key messages
While vaccines against a number of pathogens have been studied for their ability to reduce antimicrobial use, currently only vaccination against influenza or pneumococcus has generated sufficient data for analysis
Vaccination against either influenza or pneumococcus significantly reduced overall antimicrobial prescribing rates, both in vaccinated individuals and at a population level
Maintaining and expanding vaccination coverage thus appears to be a key tool for antimicrobial stewardship
A meta-analysis study design was used to analyze 7 data sets of invasive and carriage pneumococcal isolates recovered from children, to determine whether invasive disease potential differs for each ...serotype and, if so, whether it has changed over time or differs geographically. Serotype- and serogroup-specific odds ratios (ORs) were calculated for each study and as a pooled estimate, with use of serotype 14 as the reference group. ORs varied widely: the serotypes with the highest ORs (1, 5, and 7) were 60-fold more invasive than those with the lowest ORs (3, 6A, and 15). There was a significant inverse correlation between invasive disease and carriage prevalence for the serotypes that we considered, which implies that the most invasive serotypes and serogroups were the least commonly carried and that the most frequently carried were the least likely to cause invasive disease. There was no evidence of any temporal change or major geographical differences in serotype- or serogroup-specific invasive disease potential.
Recently, two related
strains with reduced susceptibility to ampicillin, amoxicillin, and cefotaxime, antibiotics commonly used to treat
infections, were reported. The two strains had the same ...nonsynonymous (amino acid-substituting) mutation in the
gene, encoding penicillin-binding protein 2X (PBP2X). This concerning report led us to investigate our library of 7,025 genome sequences of type
,
, and
clinical strains recovered from intercontinental sources for mutations in
We identified 137 strains that, combined, had 37 nonsynonymous mutations in 36 codons in
Although to a lesser magnitude than the two previously published isolates, many of our strains had decreased susceptibility
to multiple beta-lactam antibiotics. Many
mutations were found only in single strains, but 16 groups of two or more isolates of the same
type had an identical amino acid replacement. Phylogenetic analysis showed that, with one exception, strains of the same
type with the same amino acid replacement were clonally related by descent. This finding indicates that strains with some amino acid changes in PBP2X can successfully spread to new human hosts and cause invasive infections. Mapping of the amino acid changes onto a three-dimensional structure of the related
PBP2X suggests that some substitutions are located in regions functionally important in related pathogenic bacterial species. Decreased beta-lactam susceptibility is geographically widespread in strains of numerically common
gene subtypes. Enhanced surveillance and further epidemiological and molecular genetic study of this potential emergent antimicrobial problem are warranted.
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