#Pneumococcal susceptibility to #antibiotics in #carriage: a 17 year time series analysis of the adaptive #evolution of non-vaccine emerging #serotypes to a new selective pressure environment (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Pneumococcal susceptibility to antibiotics in carriage: a 17 year time series analysis of the adaptive evolution of non-vaccine emerging serotypes to a new selective pressure environment

Naim Ouldali, Robert Cohen, Corinne Levy, Nathalie Gelbert-Baudino, Elisa Seror. François Corrard, François Vie Le Sage, Anne-Sylvestre Michot, Olivier Romain, Stéphane Bechet, Stéphane Bonacorsi, François Angoulvant, Emmanuelle Varon

Journal of Antimicrobial Chemotherapy, dkz281, https://doi.org/10.1093/jac/dkz281

Published: 06 July 2019

 

Abstract

Background

Pneumococcal conjugate vaccine (PCV) implementations led to major changes in serotype distribution and antibiotic resistance in carriage, accompanied by changes in antibiotic consumption.

Objectives

To assess the dynamic patterns of antimicrobial non-susceptibility across non-PCV13 serotypes following PCV implementations.

Methods

We conducted a quasi-experimental interrupted time series analysis based on a 17 year French nationwide prospective cohort. From 2001 to 2018, 121 paediatricians obtained nasopharyngeal swabs from children with acute otitis media who were aged 6 months to 2 years. The main outcome was the rate of penicillin-non-susceptible pneumococci (PNSP), analysed by segmented regression.

Results

We enrolled 10 204 children. After PCV13 implementation, the PNSP rate decreased (−0.5% per month; 95% CI −0.9 to −0.1), then, after 2014, the rate slightly increased (+0.7% per month; 95% CI +0.2 to +1.2). Global antibiotic use within the previous 3 months decreased over the study period (−22.2%; 95% CI −33.0 to −11.3), but aminopenicillin use remained high. Among the main non-PCV13 serotypes, four dynamic patterns of penicillin susceptibility evolution were observed, including unexpected patterns of serotypes emerging while remaining or even becoming penicillin susceptible. In contrast to PNSP strains, for these latter patterns, the rate of co-colonization with Haemophilus influenzae increased concomitant with their emergence.

Conclusions

In a context of continuing high antibiotic selective pressure, a progressive increase in PNSP rate was observed after 2014. However, we highlighted an unexpected variability in dynamic patterns of penicillin susceptibility among emerging non-PCV13 serotypes. Antibiotic resistance may not be the only adaptive mechanism to antimicrobial selective pressure, and co-colonization with H. influenzae may be involved.

Issue Section: ORIGINAL RESEARCH

© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Antibiotics; Drugs Resistance; Penicillin; Streptococcus pneumoniae; Vaccines; Haemophilus Influenzae.

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Causes of severe #pneumonia requiring #hospital admission in #children without HIV infection from #Africa and #Asia: the #PERCH multi-country case-control study (Lancet, abstract)

[Source: The Lancet, full page: (LINK). Abstract, edited.]

Causes of severe pneumonia requiring hospital admission in children without HIV infection from Africa and Asia: the PERCH multi-country case-control study

The Pneumonia Etiology Research for Child Health (PERCH) Study Group †

Open Access / Published: June 27, 2019 / DOI: https://doi.org/10.1016/S0140-6736(19)30721-4

 

Summary

Background

Pneumonia is the leading cause of death among children younger than 5 years. In this study, we estimated causes of pneumonia in young African and Asian children, using novel analytical methods applied to clinical and microbiological findings.

Methods

We did a multi-site, international case-control study in nine study sites in seven countries: Bangladesh, The Gambia, Kenya, Mali, South Africa, Thailand, and Zambia. All sites enrolled in the study for 24 months. Cases were children aged 1–59 months admitted to hospital with severe pneumonia. Controls were age-group-matched children randomly selected from communities surrounding study sites. Nasopharyngeal and oropharyngeal (NP-OP), urine, blood, induced sputum, lung aspirate, pleural fluid, and gastric aspirates were tested with cultures, multiplex PCR, or both. Primary analyses were restricted to cases without HIV infection and with abnormal chest x-rays and to controls without HIV infection. We applied a Bayesian, partial latent class analysis to estimate probabilities of aetiological agents at the individual and population level, incorporating case and control data.

Findings

Between Aug 15, 2011, and Jan 30, 2014, we enrolled 4232 cases and 5119 community controls. The primary analysis group was comprised of 1769 (41·8% of 4232) cases without HIV infection and with positive chest x-rays and 5102 (99·7% of 5119) community controls without HIV infection. Wheezing was present in 555 (31·7%) of 1752 cases (range by site 10·6–97·3%). 30-day case-fatality ratio was 6·4% (114 of 1769 cases). Blood cultures were positive in 56 (3·2%) of 1749 cases, and Streptococcus pneumoniae was the most common bacteria isolated (19 [33·9%] of 56). Almost all cases (98·9%) and controls (98·0%) had at least one pathogen detected by PCR in the NP-OP specimen. The detection of respiratory syncytial virus (RSV), parainfluenza virus, human metapneumovirus, influenza virus, S pneumoniae, Haemophilus influenzae type b (Hib), H influenzae non-type b, and Pneumocystis jirovecii in NP-OP specimens was associated with case status. The aetiology analysis estimated that viruses accounted for 61·4% (95% credible interval [CrI] 57·3–65·6) of causes, whereas bacteria accounted for 27·3% (23·3–31·6) and Mycobacterium tuberculosis for 5·9% (3·9–8·3). Viruses were less common (54·5%, 95% CrI 47·4–61·5 vs 68·0%, 62·7–72·7) and bacteria more common (33·7%, 27·2–40·8 vs 22·8%, 18·3–27·6) in very severe pneumonia cases than in severe cases. RSV had the greatest aetiological fraction (31·1%, 95% CrI 28·4–34·2) of all pathogens. Human rhinovirus, human metapneumovirus A or B, human parainfluenza virus, S pneumoniae, M tuberculosis, and H influenzae each accounted for 5% or more of the aetiological distribution. We observed differences in aetiological fraction by age for Bordetella pertussis, parainfluenza types 1 and 3, parechovirus–enterovirus, P jirovecii, RSV, rhinovirus, Staphylococcus aureus, and S pneumoniae, and differences by severity for RSV, S aureus, S pneumoniae, and parainfluenza type 3. The leading ten pathogens of each site accounted for 79% or more of the site’s aetiological fraction.

Interpretation

In our study, a small set of pathogens accounted for most cases of pneumonia requiring hospital admission. Preventing and treating a subset of pathogens could substantially affect childhood pneumonia outcomes.

Funding

Bill & Melinda Gates Foundation.

Keywords: Pneumonia; Pediatrics; Africa; Asia; Streptococcus pneumoniae; RSV; Metapneumovirus; Seasonal Influenza.

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Interaction with nontypeable #Haemophilus influenzae alters progression of #Streptococcus pneumoniae serotypes from colonization to upper #respiratory tract #diseases in #children in a site-specific manner (J Infect dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

Interaction with nontypeable Haemophilus influenzae alters progression of Streptococcus pneumoniae serotypes from colonization to upper respiratory tract diseases in children in a site-specific manner

Joseph A Lewnard, Noga Givon-Lavi, Ron Dagan

The Journal of Infectious Diseases, jiz312, https://doi.org/10.1093/infdis/jiz312

Published: 22 June 2019

 

Abstract

Introduction

Pneumococci and nontypeable Haemophilusinfluenzae (NTHi) often co-colonize children. The impact of species interactions on disease risk across the upper respiratory mucosa is not known.

Methods

We analyzed data from 4,104 acute conjunctivitis (AC) cases, 11,767 otitis media (OM) cases, and 1,587 nasopharyngeal specimens collected from Israeli children before pneumococcal conjugate vaccine introduction. We compared pneumococcal serotype distributions with NTHi present and absent, and compared single-species and mixed-species rates of serotype-specific progression from colonization to AC and OM.

Results

Pneumococcal serotypes causing single-species OM (NTHi absent) were less diverse than colonizing serotypes, and also less diverse than those causing mixed-species OM; colonizing and OM-causing pneumococcal serotype distributions were more similar to each other with NTHi present than with NTHi absent. In contrast, serotype diversity did not differ appreciably between colonizing and AC-causing pneumococci, regardless of NTHi co-occurrence. The similarity of colonizing and AC-causing pneumococcal serotype distributions was consistent in the presence and absence of NTHi. Differences in rates that pneumococcal serotypes progressed from colonization to disease were reduced in both AC and OM when NTHi was present.

Conclusions

Interactions with NTHi may alter progression of pneumococcal serotypes to diseases of the upper respiratory mucosa in a site-specific manner.

Streptococcus pneumoniae, nontypeable Haemophilus influenzae, otitis media, acute connunctivitis, nasopharynx, carriage

Issue Section: Major Article

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© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Haemophilus Influenzae; Streptococcus pneumoniae; Pediatrics.

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#Pneumococcal #lineages associated with serotype #replacement and #antibiotic #resistance in #childhood #IPD in the post- #PCV13 era: an international #WGS study (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Pneumococcal lineages associated with serotype replacement and antibiotic resistance in childhood invasive pneumococcal disease in the post-PCV13 era: an international whole-genome sequencing study

Stephanie W Lo, PhD  *,  Rebecca A Gladstone, PhD *, Andries J van Tonder, DPhil, John A Lees, PhD, Mignon du Plessis, PhD, Rachel Benisty, PhD, Noga Givon-Lavi, PhD, Paulina A Hawkins, MPH, Jennifer E Cornick, PhD, Brenda Kwambana-Adams, PhD, Pierra Y Law, PhD, Pak Leung Ho, MD, Martin Antonio, PhD, Dean B Everett, PhD, Prof Ron Dagan, MD, Anne von Gottberg, PhD, Prof Keith P Klugman, MD, Lesley McGee, PhD, Prof Robert F Breiman, MD, Stephen D Bentley, PhD,  The Global Pneumococcal Sequencing Consortium

Open Access / Published: June 10, 2019 / DOI: https://doi.org/10.1016/S1473-3099(19)30297-X

 

Summary

Background

Invasive pneumococcal disease remains an important health priority owing to increasing disease incidence caused by pneumococci expressing non-vaccine serotypes. We previously defined 621 Global Pneumococcal Sequence Clusters (GPSCs) by analysing 20 027 pneumococcal isolates collected worldwide and from previously published genomic data. In this study, we aimed to investigate the pneumococcal lineages behind the predominant serotypes, the mechanism of serotype replacement in disease, as well as the major pneumococcal lineages contributing to invasive pneumococcal disease in the post-vaccine era and their antibiotic resistant traits.

Methods

We whole-genome sequenced 3233 invasive pneumococcal disease isolates from laboratory-based surveillance programmes in Hong Kong (n=78), Israel (n=701), Malawi (n=226), South Africa (n=1351), The Gambia (n=203), and the USA (n=674). The genomes represented pneumococci from before and after pneumococcal conjugate vaccine (PCV) introductions and were from children younger than 3 years. We identified predominant serotypes by prevalence and their major contributing lineages in each country, and assessed any serotype replacement by comparing the incidence rate between the pre-PCV and PCV periods for Israel, South Africa, and the USA. We defined the status of a lineage as vaccine-type GPSC (≥50% 13-valent PCV [PCV13] serotypes) or non-vaccine-type GPSC (>50% non-PCV13 serotypes) on the basis of its initial serotype composition detected in the earliest vaccine period to measure their individual contribution toward serotype replacement in each country. Major pneumococcal lineages in the PCV period were identified by pooled incidence rate using a random effects model.

Findings

The five most prevalent serotypes in the PCV13 period varied between countries, with only serotypes 5, 12F, 15B/C, 19A, 33F, and 35B/D common to two or more countries. The five most prevalent serotypes in the PCV13 period varied between countries, with only serotypes 5, 12F, 15B/C, 19A, 33F, and 35B/D common to two or more countries. These serotypes were associated with more than one lineage, except for serotype 5 (GPSC8). Serotype replacement was mainly mediated by expansion of non-vaccine serotypes within vaccine-type GPSCs and, to a lesser extent, by increases in non-vaccine-type GPSCs. A globally spreading lineage, GPSC3, expressing invasive serotypes 8 in South Africa and 33F in the USA and Israel, was the most common lineage causing non-vaccine serotype invasive pneumococcal disease in the PCV13 period. We observed that same prevalent non-vaccine serotypes could be associated with distinctive lineages in different countries, which exhibited dissimilar antibiotic resistance profiles. In non-vaccine serotype isolates, we detected significant increases in the prevalence of resistance to penicillin (52 [21%] of 249 vs 169 [29%] of 575, p=0·0016) and erythromycin (three [1%] of 249 vs 65 [11%] of 575, p=0·0031) in the PCV13 period compared with the pre-PCV period.

Interpretation

Globally spreading lineages expressing invasive serotypes have an important role in serotype replacement, and emerging non-vaccine serotypes associated with different pneumococcal lineages in different countries might be explained by local antibiotic-selective pressures. Continued genomic surveillance of the dynamics of the pneumococcal population with increased geographical representation in the post-vaccine period will generate further knowledge for optimising future vaccine design.

Funding

Bill & Melinda Gates Foundation, Wellcome Sanger Institute, and the US Centers for Disease Control.

Keywords: Antibiotics; Drugs Resistance; S. Pneumoniae; Vaccines.

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Non-lytic #antibiotic #treatment in community-acquired #pneumococcal #pneumonia does not attenuate inflammation: the #PRISTINE trial (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Non-lytic antibiotic treatment in community-acquired pneumococcal pneumonia does not attenuate inflammation: the PRISTINE trial

Geert H Groeneveld, Tanny J van der Reyden, Simone A Joosten, Hester J Bootsma, Christa M Cobbaert Jutte, J C de Vries, Ed J Kuijper, Jaap T van Dissel

Journal of Antimicrobial Chemotherapy, dkz207, https://doi.org/10.1093/jac/dkz207

Published: 18 May 2019

 

Abstract

Background

The inflammatory response in pneumococcal infection is primarily driven by immunoreactive bacterial cell wall components [lipoteichoic acid (LTA)]. An acute release of these components occurs when pneumococcal infection is treated with β-lactam antibiotics.

Objectives

We hypothesized that non-lytic rifampicin compared with lytic β-lactam antibiotic treatment would attenuate the inflammatory response in patients with pneumococcal pneumonia.

Methods

In the PRISTINE (Pneumonia treated with RIfampicin aTtenuates INflammation) trial, a randomized, therapeutic controlled, exploratory study in patients with community-acquired pneumococcal pneumonia, we looked at LTA release and inflammatory and clinical response during treatment with both rifampicin and β-lactam compared with treatment with β-lactam antibiotics only. The trial is registered in the Dutch trial registry, number NTR3751 (European Clinical Trials Database number 2012-003067-22).

Results

Forty-one patients with community-acquired pneumonia were included; 17 of them had pneumococcal pneumonia. LTA release, LTA-mediated inflammatory responses, clinical outcomes, inflammatory biomarkers and transcription profiles were not different between treatment groups.

Conclusions

The PRISTINE study demonstrated the feasibility of adding rifampicin to β-lactam antibiotics in the treatment of community-acquired pneumococcal pneumonia, but, despite solid in vitro and experimental animal research evidence, failed to demonstrate a difference in plasma LTA concentrations and subsequent inflammatory and clinical responses. Most likely, an inhibitory effect of human plasma contributes to the low immune response in these patients. In addition, LTA plasma concentration could be too low to mount a response via Toll-like receptor 2 in vitro, but may nonetheless have an effect in vivo.

Topic: antibiotics – rifampin – inflammation – immune response – community acquired  pneumonia – biological markers – cell wall – lactams – plasma – pneumococcal infections – pneumonia, pneumococcal – treatment outcome – inflammatory response – community – toll-like receptor 2 – attenuation

Issue Section: ORIGINAL RESEARCH

Keywords: Antibiotics; S. pneumoniae; Pneumonia; Beta-lactams; Rifampin.

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#Bacterial Factors Required for #Transmission of #Streptococcus pneumoniae in #Mammalian Hosts (Cell Host Microbe, abstract)

[Source: Cell, Host & Microbe, full page: (LINK). Abstract, edited.]

Bacterial Factors Required for Transmission of Streptococcus pneumoniae in Mammalian Hosts

Hannah M. Rowe, Erik Karlsson, Haley Echlin, Ti-Cheng Chang, Lei Wang, Tim van Opijnen, Stanley B. Pounds, Stacey Schultz-Cherry, Jason W. Rosch

Published: May 21, 2019 / DOI: https://doi.org/10.1016/j.chom.2019.04.012

 

Highlights

  • A pneumococcal Tn-seq library was screened in a ferret transmission model
  • The fitness landscape of S. pneumoniae genes during mammalian transmission established
  • Metabolic factors enhance pneumococcal environmental stability
  • Vaccinating dams with identified factors blocks pneumococcal transmission in offspring

 

Summary

The capacity of Streptococcus pneumoniae to successfully transmit and colonize new human hosts is a critical aspect of pneumococcal population biology and a prerequisite for invasive disease. However, the bacterial mechanisms underlying this process remain largely unknown. To identify bacterial factors required for transmission, we conducted a high-throughput genetic screen with a transposon sequencing (Tn-seq) library of a pneumococcal strain in a ferret transmission model. Key players in both metabolism and transcriptional regulation were identified as required for efficient bacterial transmission. Targeted deletion of the putative C3-degrading protease CppA, iron transporter PiaA, or competence regulatory histidine kinase ComD significantly decreased transmissibility in a mouse model, further validating the screen. Maternal vaccination with recombinant surface-exposed PiaA and CppA alone or in combination blocked transmission in offspring and were more effective than capsule-based vaccines. These data underscore the possibility of targeting pneumococcal transmission as a means of eliminating invasive disease in the population.

Keywords: Streptococcus pneumoniae – transmission – ferret – influenza

Keywords: Streptococcus pneumoniae; IPD; Animal models.

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#Risk modeling the #mortality impact of #antimicrobial #resistance in secondary #pneumococcal #pneumonia infections during the 2009 #influenza #pandemic (Int J Infect Dis., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Int J Infect Dis. 2019 May 13. pii: S1201-9712(19)30211-5. doi: 10.1016/j.ijid.2019.05.005. [Epub ahead of print]

Risk modeling the mortality impact of antimicrobial resistance in secondary pneumococcal pneumonia infections during the 2009 influenza pandemic.

Barnes CE1, MacIntyre CR2.

Author information: 1 School of Public Health and Community Medicine, University of New South Wales, Sydney, Australia. Electronic address: barnes103@hotmail.com. 2 School of Public Health and Community Medicine, University of New South Wales, Sydney, Australia; The Kirby Institute, Sydney, Australia. Electronic address: r.macintyre@unsw.edu.au.

 

Abstract

OBJECTIVES:

The aim of this study was to estimate the impact of antimicrobial resistance (AMR) in secondary pneumococcal pneumonia infections on global mortality during the 2009 influenza pandemic, to estimate future pandemic mortality risk and to inform pandemic preparedness.

METHODS:

Risk analysis modeling was conducted using a multivariate risk formula. Literature reviews were conducted to generate global central estimates for each of the parameters of the risk formula in relation to the 2009 influenza pandemic, secondary pneumococcal pneumonia, rates of AMR and pneumococcal vaccine efficacy as a component of pandemic preparedness.

RESULTS:

Global Streptococcus pneumoniae AMR was estimated at 21.8% to 27.6%, and contributed to 1.8% to 2.3% of deaths during the 2009 influenza pandemic. When directly applied to mortality due to multidrug resistance, pneumococcal vaccination could potentially prevent 1,277 to 3,754 deaths and could have reduced mortality from multidrug resistant S. pneumoniae to 1% to 1.2%.

CONCLUSION:

AMR in secondary pneumococcal infections contributed towards a small percentage of the global mortality during the 2009 influenza pandemic. Increased S. pnuemoniae AMR could result in a three- to four-fold rise in mortality due to secondary pneumococcal infections in future influenza pandemics. Pneumococcal vaccination has an important role in preventing pneumococcal co-infections and combating AMR in all populations, and should be considered a key component of influenza pandemic preparedness or early action plans.

Copyright © 2019. Published by Elsevier Ltd.

KEYWORDS: Streptococcus pneumoniae; antimicrobial resistance; pandemic influenza; secondary pneumococcal pneumonia

PMID: 31096052 DOI: 10.1016/j.ijid.2019.05.005

Keywords: Pandemic Influenza; Streptococcus pneumoniae; Vaccines; Antibiotics; Drugs Resistance.

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