scholarly journals A pneumococcal controlled human infection model in Malawi: Transfer of an established pneumococcal carriage model from Liverpool, UK to Blantyre, Malawi – A feasibility study

2020 ◽  
Vol 5 ◽  
pp. 25
Author(s):  
Ben Morton ◽  
Sarah Burr ◽  
Kondwani Jambo ◽  
Jamie Rylance ◽  
Marc Y.R. Henrion ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Feasibility Study ◽  
Invasive Disease ◽  
Community Acquired Pneumonia ◽  
Human Infection ◽  
Infection Model ◽  
Endpoint Detection ◽  
Pneumococcal Carriage ◽  
Sampling Protocols ◽  
Classical Culture

Streptococcus pneumoniae is the leading cause of morbidity and mortality due to community acquired pneumonia, bacterial meningitis and bacteraemia worldwide. Pneumococcal conjugate vaccines protect against invasive disease, but are expensive to manufacture, limited in serotype coverage, associated with serotype replacement and demonstrate reduced effectiveness against mucosal colonisation.  As asymptomatic colonisation of the human nasopharynx is a prerequisite for pneumococcal disease, this is proposed as a marker for novel vaccine efficacy. Our team established a safe and reproducible pneumococcal controlled human infection model at Liverpool School of Tropical Medicine (LSTM). This has been used to test vaccine induced protection against nasopharyngeal carriage for ten years in over 1000 participants. We will transfer established standardised operating procedures from LSTM to Malawi and test in up to 36 healthy participants. Primary endpoint: detection of the inoculated pneumococci by classical culture from nasal wash recovered from the participants after pneumococcal challenge. Secondary endpoints: confirmation of robust clinical and laboratory methods for sample capture and processing. Tertiary endpoints: participant acceptability of study and methods. We will test three doses of pneumococcal inoculation (20,000, 80,000 and 160,000 colony forming units [CFUs] per naris) using a parsimonious study design intended to reduce unnecessary exposure to participants. We hypothesise that 80,000 CFUs will induce nasal colonisation in approximately half of participants per established LSTM practice. The aims of the feasibility study are: 1) Establish Streptococcus pneumoniae experimental human pneumococcal carriage in Malawi; 2) Confirm optimal nasopharyngeal pneumococcal challenge dose; 3) Confirm safety and measure potential symptoms; 4) Confirm sampling protocols and laboratory assays; 5) Assess feasibility and acceptability of consent and study procedures. Confirmation of pneumococcal controlled human infection model feasibility in Malawi will enable us to target pneumococcal vaccine candidates for an at-risk population who stand the most to gain from new and improved vaccine strategies.

scholarly journals A pneumococcal controlled human infection model in Malawi: Transfer of an established pneumococcal carriage model from Liverpool, UK to Blantyre, Malawi – A feasibility study

2020 ◽  
Vol 5 ◽  
pp. 25
Author(s):  
Ben Morton ◽  
Sarah Burr ◽  
Kondwani Jambo ◽  
Jamie Rylance ◽  
Marc Y.R. Henrion ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Feasibility Study ◽  
Invasive Disease ◽  
Community Acquired Pneumonia ◽  
Human Infection ◽  
Infection Model ◽  
Endpoint Detection ◽  
Pneumococcal Carriage ◽  
Sampling Protocols ◽  
Classical Culture

Streptococcus pneumoniae is the leading cause of morbidity and mortality due to community acquired pneumonia, bacterial meningitis and bacteraemia worldwide. Pneumococcal conjugate vaccines protect against invasive disease, but are expensive to manufacture, limited in serotype coverage, associated with serotype replacement and demonstrate reduced effectiveness against mucosal colonisation.  As asymptomatic colonisation of the human nasopharynx is a prerequisite for pneumococcal disease, this is proposed as a marker for novel vaccine efficacy. Our team established a safe and reproducible pneumococcal controlled human infection model at Liverpool School of Tropical Medicine (LSTM). This has been used to test vaccine induced protection against nasopharyngeal carriage for ten years in over 1000 participants. We will transfer established standardised operating procedures from LSTM to Malawi and test in up to 36 healthy participants. Primary endpoint: detection of the inoculated pneumococci by classical culture from nasal wash recovered from the participants after pneumococcal challenge. Secondary endpoints: confirmation of robust clinical and laboratory methods for sample capture and processing. Tertiary endpoints: participant acceptability of study and methods. We will test three doses of pneumococcal inoculation (20,000, 80,000 and 160,000 colony forming units [CFUs] per naris) using a parsimonious study design intended to reduce unnecessary exposure to participants. We hypothesise that 80,000 CFUs will induce nasal colonisation in approximately half of participants per established LSTM practice. The aims of the feasibility study are: 1) Establish Streptococcus pneumoniae experimental human pneumococcal carriage in Malawi; 2) Confirm optimal nasopharyngeal pneumococcal challenge dose; 3) Confirm safety and measure potential symptoms; 4) Confirm sampling protocols and laboratory assays; 5) Assess feasibility and acceptability of consent and study procedures. Confirmation of pneumococcal controlled human infection model feasibility in Malawi will enable us to target pneumococcal vaccine candidates for an at-risk population who stand the most to gain from new and improved vaccine strategies.

scholarly journals In Vitro Infection Model Characterizing the Effect of Efflux Pump Inhibition on Prevention of Resistance to Levofloxacin and Ciprofloxacin in Streptococcus pneumoniae

2007 ◽  
Vol 51 (11) ◽  
pp. 3988-4000 ◽  
Author(s):  
Arnold Louie ◽  
David L. Brown ◽  
Weiguo Liu ◽  
Robert W. Kulawy ◽  
Mark R. Deziel ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Efflux Pump ◽  
Community Acquired Pneumonia ◽  
Fluoroquinolone Resistance ◽  
Infection Model ◽  
Wild Type ◽  
Efflux Pump Inhibition ◽  
Short Term Exposure ◽  
Emergence Of Resistance

ABSTRACT The prevalence of fluoroquinolone-resistant Streptococcus pneumoniae is slowly rising as a consequence of the increased use of fluoroquinolone antibiotics to treat community-acquired pneumonia. We tested the hypothesis that increased efflux pump (EP) expression by S. pneumoniae may facilitate the emergence of fluoroquinolone resistance. By using an in vitro pharmacodynamic infection system, a wild-type S. pneumoniae strain (Spn-058) and an isogenic strain with EP overexpression (Spn-RC2) were treated for 10 days with ciprofloxacin or levofloxacin in the presence or absence of the EP inhibitor reserpine to evaluate the effect of EP inhibition on the emergence of resistance. Cultures of Spn-058 and Spn-RC2 were exposed to concentration-time profiles simulating those in humans treated with a regimen of ciprofloxacin at 750 mg orally once every 12 h and with regimens of levofloxacin at 500 and 750 mg orally once daily (QD; with or without continuous infusions of 20 μg of reserpine/ml). The MICs of ciprofloxacin and levofloxacin for Spn-058 were both 1 μg/ml when susceptibility testing was conducted with each antibiotic alone and with each antibiotic in the presence of reserpine. For Spn-RC2, the MIC of levofloxacin alone and with reserpine was also 1 μg/ml; the MICs of ciprofloxacin were 2 and 1 μg/ml, respectively, when determined with ciprofloxacin alone and in combination with reserpine. Reserpine, alone, had no effect on the growth of Spn-058 and Spn-RC2. For Spn-058, simulated regimens of ciprofloxacin at 750 mg every 12 h or levofloxacin at 500 mg QD were associated with the emergence of fluoroquinolone resistance. However, the use of ciprofloxacin at 750 mg every 12 h and levofloxacin at 500 mg QD in combination with reserpine rapidly killed Spn-058 and prevented the emergence of resistance. For Spn-RC2, levofloxacin at 500 mg QD was associated with the emergence of resistance, but again, the resistance was prevented when this levofloxacin regimen was combined with reserpine. Ciprofloxacin at 750 mg every 12 h also rapidly selected for ciprofloxacin-resistant mutants of Spn-RC2. However, the addition of reserpine to ciprofloxacin therapy only delayed the emergence of resistance. Levofloxacin at 750 mg QD, with and without reserpine, effectively eradicated Spn-058 and Spn-RC2 without selecting for fluoroquinolone resistance. Ethidium bromide uptake and efflux studies demonstrated that, at the baseline, Spn-RC2 had greater EP expression than Spn-058. These studies also showed that ciprofloxacin was a better inducer of EP expression than levofloxacin in both Spn-058 and Spn-RC2. However, in these isolates, the increase in EP expression by short-term exposure to ciprofloxacin and levofloxacin was transient. Mutants of Spn-058 and Spn-RC2 that emerged under suboptimal antibiotic regimens had a stable increase in EP expression. Levofloxacin at 500 mg QD in combination with reserpine, an EP inhibitor, or at 750 mg QD alone killed wild-type S. pneumoniae and strains that overexpressed reserpine-inhibitable EPs and was highly effective in preventing the emergence of fluoroquinolone resistance in S. pneumoniae during therapy. Ciprofloxacin at 750 mg every 12 h, as monotherapy, was ineffective for the treatment of Spn-058 and Spn-RC2. Ciprofloxacin in combination with reserpine prevented the emergence of resistance in Spn-058 but not in Spn-RC2, the EP-overexpressing strain.

scholarly journals The influence of pneumococcal conjugate vaccine-13 on nasal colonisation in a controlled human infection model of pneumococcal carriage in Malawi: a double-blinded randomised controlled trial protocol

2021 ◽  
Vol 6 ◽  
pp. 240
Author(s):  
Ben Morton ◽  
Kondwani Jambo ◽  
Tarsizio Chikaonda ◽  
Jamie Rylance ◽  
Marc Y.R. Henrion ◽  
...  
Keyword(s):  
Randomised Controlled Trial ◽  
Conjugate Vaccine ◽  
Pneumococcal Conjugate Vaccine ◽  
Controlled Trial ◽  
Nasal Carriage ◽  
Human Infection ◽  
Infection Model ◽  
Pneumococcal Carriage ◽  
Randomised Controlled ◽  
Double Blinded

Streptococcus pneumoniae is the leading cause of morbidity and mortality due to community acquired pneumonia, bacterial meningitis and bacteraemia worldwide. Pneumococcal conjugate vaccines protect against invasive disease, but are expensive to manufacture, limited in serotype coverage, associated with serotype replacement, and demonstrate reduced effectiveness against mucosal colonisation.  For Malawi, nasopharyngeal carriage of vaccine-type pneumococci is common in vaccinated children despite national roll-out of 13-valent pneumococcal conjugate vaccine (PCV13) since 2011. Our team has safely transferred an established experimental human pneumococcal carriage method from Liverpool School of Tropical Medicine to the Malawi-Liverpool Wellcome Trust Clinical Research Programme, Malawi. This study will determine potential immunological mechanisms for the differential effects of PCV13 on nasal carriage between healthy Malawian and UK populations. We will conduct a double-blinded randomised controlled trial to vaccinate (1:1) participants with either PCV13 or control (normal saline). After a period of one month, participants will be inoculated with S. pneumoniae serotype 6B to experimentally induce nasal carriage using the EHPC method. Subsequently, participants will be invited for a second inoculation after one year to determine longer-term vaccine-induced immunological effects. Primary endpoint: detection of inoculated pneumococci by classical culture from nasal wash recovered from the participants after pneumococcal challenge. Secondary endpoints: local and systemic innate, humoral and cellular responses to PCV-13 with and without pneumococcal nasal carriage The primary objective of this controlled human infection model study is to determine if PCV-13 vaccination is protective against pneumococcal carriage in healthy adult Malawian volunteers. This study will help us to understand the observed differences in PCV-13 efficacy between populations and inform the design of future vaccines relevant to the Malawian population. Trial Registration: Pan African Clinical Trial Registry (REF: PACTR202008503507113)

scholarly journals Pharmacokinetics and Pharmacodynamics of Nemonoxacin in a Neutropenic Murine Lung Infection Model Against Streptococcus Pneumoniae

2021 ◽  
Vol 12 ◽  
Author(s):  
Xin Li ◽  
Yuancheng Chen ◽  
Xiaoyong Xu ◽  
Yi Li ◽  
Yaxin Fan ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Subcutaneous Administration ◽  
Lung Infection ◽  
Community Acquired Pneumonia ◽  
Dose Fractionation ◽  
Infection Model ◽  
Maximum Plasma ◽  
Time Curve ◽  
Murine Lung ◽  
Drug Plasma

Nemonoxacin, a novel nonfluorinated quinolone for the treatment of community-acquired pneumonia. We reported the pharmacokinetic/pharmacodynamic (PK/PD) targets and PK/PD breakpoints of nemonoxacin against Streptococcus pneumoniae using a neutropenic murine lung infection model. Single-dose PK analysis after subcutaneous administration of nemonoxacin at doses from 2.5 to 80 mg/kg showed maximum plasma concentration (Cmax) 0.56–7.32 mg/L, area under the concentration-time curve from 0 to 24 h (AUC0-24) 0.67–26.10 mg·h/L, and elimination half-life (T1/2) 0.8–1.4 h. The epithelial lining fluid (ELF) penetration ratio of total drug was 1.40. Dose fractionation (1.25–80 mg/kg/day, every 24, 12, 8, and 6 h) and dose escalation studies (1.25–160 mg/kg, every 24 h) were conducted. The sigmoid Emax Hill equation was used to describe the dose-response data. The free-drug plasma fAUC0-24/MIC ratio was considered the PK/PD index most closely associated with efficacy (R2 0.9268). Median fAUC0-24/MIC associated with static, 1-log10 and 2-log10 CFU reduction from baseline were 8.6, 23.2 and 44.4, respectively. Monte Carlo simulation showed 500 mg qd and 750 mg qd oral doses of nemonoxacin were able to achieve 90% probability of target attainment (PTA) against bacteria with MIC of 0.5 mg/L and 1 mg/L. We recommended susceptibility (S) ≤ 0.5 mg/L, intermediate (I) = 1 mg/L and resistant (R) ≥ 2 mg/L as the PK/PD breakpoints for nemonoxacin against S. pneumoniae.

scholarly journals Intestinal helminth co-infection is an unrecognised risk factor for increased pneumococcal carriage density and invasive disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alice E. Law ◽  
Rebecca K. Shears ◽  
Andrea A. Lopez Rodas ◽  
Richard K. Grencis ◽  
Philip J. Cooper ◽  
...  
Keyword(s):  
Risk Factor ◽  
Cost Effective ◽  
Invasive Disease ◽  
Intestinal Helminth ◽  
Infection Model ◽  
Pneumococcal Carriage ◽  
Helminth Infections ◽  
Cost Effective Method ◽  
Lower Income Countries ◽  
The Impact

AbstractInfection with Streptococcus pneumoniae is the leading cause of death in children and burden of disease is greatest where helminth infections are also common. We investigated the impact of intestinal helminth co-infection on pneumococcal carriage; a risk factor for invasive disease. We used a mouse co-infection model and clinical data to assess the impact of co-infection on carriage density. Co-infection in mice was associated with increased pneumococcal carriage density and dissemination into lungs. Helminth-infected children also exhibited increased carriage density as compared to uninfected children. Anthelmintic treatment may be a cost-effective method of reducing pneumococcal disease burden in lower-income countries.

scholarly journals A feasibility study of controlled human infection with Streptococcus pneumoniae in Malawi

EBioMedicine ◽  
2021 ◽  
Vol 72 ◽  
pp. 103579 ◽  
Author(s):  
Ben Morton ◽  
Sarah Burr ◽  
Tarsizio Chikaonda ◽  
Edna Nsomba ◽  
Lucinda Manda-Taylor ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Feasibility Study ◽  
Human Infection

DiiA is a novel dimorphic cell wall protein of Streptococcus pneumoniae involved in invasive disease

2016 ◽  
Vol 73 (1) ◽  
pp. 71-81 ◽  
Author(s):  
María S. Escolano-Martínez ◽  
Arnau Domenech ◽  
José Yuste ◽  
María I. Cercenado ◽  
Carmen Ardanuy ◽  
...  
Keyword(s):  
Cell Wall ◽  
Streptococcus Pneumoniae ◽  
Invasive Disease ◽  
Cell Wall Protein

scholarly journals Control of Mucosal Candidiasis in the Zebrafish Swim Bladder Depends on Neutrophils That Block Filament Invasion and Drive Extracellular-Trap Production

2017 ◽  
Vol 85 (9) ◽  
Author(s):  
Remi L. Gratacap ◽  
Allison K. Scherer ◽  
Brittany G. Seman ◽  
Robert T. Wheeler
Keyword(s):  
Invasive Disease ◽  
Extracellular Dna ◽  
Epithelial Barrier ◽  
Infection Model ◽  
Swim Bladder ◽  
Spatiotemporal Resolution ◽  
Zebrafish Model ◽  
Content Type ◽  
Mucosal Candidiasis ◽  
Disease Pressure

ABSTRACT Candida albicans is a ubiquitous mucosal commensal that is normally prevented from causing acute or chronic invasive disease. Neutrophils contribute to protection in oral infection but exacerbate vulvovaginal candidiasis. To dissect the role of neutrophils during mucosal candidiasis, we took advantage of a new, transparent zebrafish swim bladder infection model. Intravital microscopic tracking of individual animals revealed that the blocking of neutrophil recruitment leads to rapid mortality in this model through faster disease progression. Conversely, artificial recruitment of neutrophils during early infection reduces disease pressure. Noninvasive longitudinal tracking showed that mortality is a consequence of C. albicans breaching the epithelial barrier and invading surrounding tissues. Accordingly, we found that a hyperfilamentous C. albicans strain breaches the epithelial barrier more frequently and causes mortality in immunocompetent zebrafish. A lack of neutrophils at the infection site is associated with less fungus-associated extracellular DNA and less damage to fungal filaments, suggesting that neutrophil extracellular traps help to protect the epithelial barrier from C. albicans breach. We propose a homeostatic model where C. albicans disease pressure is balanced by neutrophil-mediated damage of fungi, maintaining this organism as a commensal while minimizing the risk of damage to host tissue. The unequaled ability to dissect infection dynamics at a high spatiotemporal resolution makes this zebrafish model a unique tool for understanding mucosal host-pathogen interactions.

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