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,

Published: 22 June 2019




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.


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.


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.


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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Keywords: Haemophilus Influenzae; Streptococcus pneumoniae; Pediatrics.


#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:




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.


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.


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.


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.


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

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


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,

Published: 18 May 2019




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.


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


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).


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.


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


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


#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:



  • 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



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.


#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: 2 School of Public Health and Community Medicine, University of New South Wales, Sydney, Australia; The Kirby Institute, Sydney, Australia. Electronic address:




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.


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.


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%.


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.


#Influenza “Trains” the Host for Enhanced Susceptibility to Secondary #Bacterial #Infection (mBio, abstract)

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

MBio. 2019 May 7;10(3). pii: e00810-19. doi: 10.1128/mBio.00810-19.

Influenza “Trains” the Host for Enhanced Susceptibility to Secondary Bacterial Infection.

Shirey KA1, Perkins DJ1, Lai W1, Zhang W2, Fernando LR2, Gusovsky F3, Blanco JCG2, Vogel SN4.

Author information: 1 Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA. 2 Sigmovir Biosystems, Inc., Rockville, Maryland, USA. 3 Eisai Inc., Andover, Massachusetts, USA. 4 Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA



We previously reported that the Toll-like receptor 4 (TLR4) antagonist Eritoran blocks acute lung injury (ALI) therapeutically in mouse and cotton rat models of influenza. However, secondary (2°) bacterial infection following influenza virus infection is associated with excess morbidity and mortality. Wild-type (WT) mice infected with mouse-adapted influenza A/Puerto Rico/8/34 virus (PR8) and, 7 days later, with Streptococcus pneumoniae serotype 3 (Sp3) exhibited significantly enhanced lung pathology and lethality that was reversed by Eritoran therapy after PR8 infection but before Sp3 infection. Cotton rats infected with nonadapted pH1N1 influenza virus and then superinfected with methicillin-resistant Staphylococcus aureus also exhibited increased lung pathology and serum high-mobility-group box 1 (HMGB1) levels, both of which were blunted by Eritoran therapy. In mice, PR8 infection suppressed Sp3-induced CXCL1 and CXCL2 mRNA, reducing neutrophil infiltration and increasing the bacterial burden, all of which were reversed by Eritoran treatment. While beta interferon (IFN-β)-deficient (IFN-β-/-) mice are highly susceptible to PR8, they exhibited delayed death upon Sp3 superinfection, indicating that while IFN-β was protective against influenza, it negatively impacted the host response to Sp3 IFN-β-treated WT macrophages selectively suppressed Sp3-induced CXCL1/CXCL2 transcriptionally, as evidenced by reduced recruitment of RNA polymerase II to the CXCL1 promoter. Thus, influenza establishes a “trained” state of immunosuppression toward 2° bacterial infection, in part through the potent induction of IFN-β and its downstream transcriptional regulation of chemokines, an effect reversed by Eritoran.



Enhanced susceptibility to 2° bacterial infections following infection with influenza virus is a global health concern that accounts for many hospitalizations and deaths, particularly during pandemics. The complexity of the impaired host immune response during 2° bacterial infection has been widely studied. Both type I IFN and neutrophil dysfunction through decreased chemokine production have been implicated as mechanisms underlying enhanced susceptibility to 2° bacterial infections. Our findings support the conclusion that selective suppression of CXCL1/CXCL2 represents an IFN-β-mediated “training” of the macrophage transcriptional response to TLR2 agonists and that blocking of TLR4 therapeutically with Eritoran after influenza virus infection reverses this suppression by blunting influenza-induced IFN-β.

Copyright © 2019 Shirey et al.

KEYWORDS: IFN-β; MRSA; Streptococcus pneumoniae; TLR4; cotton rats; influenza; macrophage training; secondary bacterial infection

PMID: 31064834 DOI: 10.1128/mBio.00810-19

Keywords: Influenza A; Streptococcus pneumoniae; Immunopathology; Animal models.


#Infant #pneumococcal carriage during #influenza, #RSV and #hMPV #respiratory illness within a #maternal influenza #immunization trial (J Infect Dis., abstract)

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

Infant pneumococcal carriage during influenza, RSV and hMPV respiratory illness within a maternal influenza immunization trial

Alastair F Murray, Janet A Englund, Jane Kuypers, James M Tielsch, Joanne Katz, Subarna K Khatry, Steven C Leclerq, Helen Y Chu

The Journal of Infectious Diseases, jiz212,

Published: 06 May 2019



In this post-hoc analysis of nasopharyngeal pneumococcal carriage in a community-based, randomized prenatal influenza vaccination trial in Nepal with weekly infant respiratory illness surveillance, 457 of 605 (75.5%) infants with influenza, RSV or hMPV illness had pneumococcus detected. Pneumococcal carriage did not impact rates of lower respiratory tract disease for these three viruses. Influenza-positive infants born to mothers given influenza vaccine had lower pneumococcal carriage rates compared to infants born to placebo mothers (58.1% versus 71.6%, p=0.03). No difference was observed in RSV- or hMPV-infected infants (p=0.94, 0.11). Maternal influenza immunization may impact infant acquisition of pneumococcus during influenza infection.

pneumococcus, influenza, vaccine, RSV, hMPV, maternal immunization

Issue Section: Brief Report

This content is only available as a PDF.

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Keywords: Seasonal Influenza; Streptococcus pneumoniae; RSV; Metapneumovirus; Vaccines; Pregnancy.