scholarly journals A Novel Zinc Binding System, ZevAB, Is Critical for Survival of Nontypeable Haemophilus influenzae in a Murine Lung Infection Model

2011 ◽  
Vol 79 (8) ◽  
pp. 3366-3376 ◽  
Author(s):  
Charles V. Rosadini ◽  
Jeffrey D. Gawronski ◽  
Daniel Raimunda ◽  
José M. Argüello ◽  
Brian J. Akerley
Keyword(s):  
Haemophilus Influenzae ◽  
Respiratory Infections ◽  
Bacterial Pathogen ◽  
Lung Infection ◽  
Lung Model ◽  
Mouse Lung ◽  
Infection Model ◽  
Nontypeable Haemophilus Influenzae ◽  
Content Type ◽  
Lung Colonization

ABSTRACTNontypeableHaemophilus influenzae(NTHI) is a Gram-negative bacterial pathogen that causes upper and lower respiratory infections. Factors required for pulmonary infection by NTHI are not well understood. Previously, using high-throughput insertion tracking by deep sequencing (HITS), putative lung colonization factors were identified. Also, previous research indicates that secreted disulfide-dependent factors are important for virulence ofH. influenzae. In the present study, HITS data were compared with an informatics-based list of putative substrates of the periplasmic oxidoreductase DsbA to find and characterize secreted virulence factors. This analysis resulted in identification of the “zinc bindingessential forvirulence” (zev) locus consisting ofzevA(HI1249) andzevB(HI1248). NTHI mutants ofzevAandzevBgrew normally in rich medium but were defective for colonization in a mouse lung model. Mutants also exhibited severe growth defects in medium containing EDTA and were rescued by supplementation with zinc. Additionally, purified recombinant ZevA was found to bind to zinc with high affinity. Together, these data demonstrate thatzevABis a novel virulence factor important for zinc utilization ofH. influenzaeunder conditions where zinc is limiting. Furthermore, evidence presented here suggests that zinc limitation is likely an important mechanism for host defense against pathogens during lung infection.

scholarly journals Molecular Characterization of Fluoroquinolone Resistance in Nontypeable Haemophilus influenzae Clinical Isolates

2014 ◽  
Vol 59 (1) ◽  
pp. 461-466 ◽  
Author(s):  
Carmen Puig ◽  
José Manuel Tirado-Vélez ◽  
Laura Calatayud ◽  
Fe Tubau ◽  
Junkal Garmendia ◽  
...  
Keyword(s):  
Haemophilus Influenzae ◽  
Nalidixic Acid ◽  
Respiratory Infections ◽  
Pulse Field ◽  
Fluoroquinolone Resistance ◽  
Chronic Obstructive ◽  
Nontypeable Haemophilus Influenzae ◽  
High Genetic Diversity ◽  
Content Type ◽  
Pulse Field Gel Electrophoresis

ABSTRACTNontypeableHaemophilus influenzae(NTHi) is a common cause of respiratory infections in adults, who are frequently treated with fluoroquinolones. The aims of this study were to characterize the genotypes of fluoroquinolone-resistant NTHi isolates and their mechanisms of resistance. Among 7,267H. influenzaeisolates collected from adult patients from 2000 to 2013, 28 (0.39%) were ciprofloxacin resistant according to Clinical and Laboratory Standards Institute (CLSI) criteria. In addition, a nalidixic acid screening during 2010 to 2013 detected five (0.23%) isolates that were ciprofloxacin susceptible but nalidixic acid resistant. Sequencing of their quinolone resistance-determining regions and genotyping by pulse-field gel electrophoresis and multilocus sequence typing of the 25 ciprofloxacin-resistant isolates available and all 5 nalidixic acid-resistant isolates were performed. In the NTHi isolates studied, two mutations producing changes in two GyrA residues (Ser84, Asp88) and/or two ParC residues (Ser84, Glu88) were associated with increased fluoroquinolone MICs. Strains with one or two mutations (n= 15) had ciprofloxacin and levofloxacin MICs of 0.12 to 2 μg/ml, while those with three or more mutations (n= 15) had MICs of 4 to 16 μg/ml. Long persistence of fluoroquinolone-resistant strains was observed in three chronic obstructive pulmonary disease patients. High genetic diversity was observed among fluoroquinolone-resistant NTHi isolates. Although fluoroquinolones are commonly used to treat respiratory infections, the proportion of resistant NTHi isolates remains low. The nalidixic acid disk test is useful for detecting the first changes in GyrA or in GyrA plus ParC among fluoroquinolone-susceptible strains that are at a potential risk for the development of resistance under selective pressure by fluoroquinolone treatment.

scholarly journals Pharmacokinetics/Pharmacodynamics of Peptide Deformylase Inhibitor GSK1322322 against Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus in Rodent Models of Infection

2015 ◽  
Vol 60 (1) ◽  
pp. 180-189 ◽  
Author(s):  
Jennifer Hoover ◽  
Thomas Lewandowski ◽  
Robert J. Straub ◽  
Steven J. Novick ◽  
Peter DeMarsh ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Streptococcus Pneumoniae ◽  
Haemophilus Influenzae ◽  
Lung Model ◽  
Peptide Deformylase ◽  
Dose Fractionation ◽  
Mouse Lung ◽  
Time Curve ◽  
Content Type

ABSTRACTGSK1322322 is a novel inhibitor of peptide deformylase (PDF) with goodin vitroactivity against bacteria associated with community-acquired pneumonia and skin infections. We have characterized thein vivopharmacodynamics (PD) of GSK1322322 in immunocompetent animal models of infection withStreptococcus pneumoniaeandHaemophilus influenzae(mouse lung model) and withStaphylococcus aureus(rat abscess model) and determined the pharmacokinetic (PK)/PD index that best correlates with efficacy and its magnitude. Oral PK studies with both models showed slightly higher-than-dose-proportional exposure, with 3-fold increases in area under the concentration-time curve (AUC) with doubling doses. GSK1322322 exhibited dose-dependentin vivoefficacy against multiple isolates ofS. pneumoniae,H. influenzae, andS. aureus. Dose fractionation studies with twoS. pneumoniaeandS. aureusisolates showed that therapeutic outcome correlated best with the free AUC/MIC (fAUC/MIC) index inS. pneumoniae(R2, 0.83), whereasfAUC/MIC and free maximum drug concentration (fCmax)/MIC were the best efficacy predictors forS. aureus(R2, 0.9 and 0.91, respectively). Median dailyfAUC/MIC values required for stasis and for a 1-log10reduction in bacterial burden were 8.1 and 14.4 for 11S. pneumoniaeisolates (R2, 0.62) and 7.2 and 13.0 for fiveH. influenzaeisolates (R2, 0.93). The data showed that for eightS. aureusisolates,fAUC correlated better with efficacy thanfAUC/MIC (R2, 0.91 and 0.76, respectively), as efficacious AUCs were similar for all isolates, independent of their GSK1322322 MIC (range, 0.5 to 4 μg/ml). MedianfAUCs of 2.1 and 6.3 μg · h/ml were associated with stasis and 1-log10reductions, respectively, forS. aureus.

scholarly journals High-Depth RNA-Seq Data Sets for Studying Gene Expression Changes Mediated by Phase-Variable DNA Methyltransferases in Nontypeable Haemophilus influenzae

2019 ◽  
Vol 8 (2) ◽  
Author(s):  
John M. Atack ◽  
Lauren O. Bakaletz ◽  
Michael P. Jennings
Keyword(s):  
Haemophilus Influenzae ◽  
Bacterial Pathogen ◽  
Dna Methyltransferases ◽  
Multiple Infections ◽  
Data Sets ◽  
Phase Variable ◽  
Rna Seq ◽  
Nontypeable Haemophilus Influenzae ◽  
Content Type ◽  
High Depth

Nontypeable Haemophilus influenzae (NTHi) is a major bacterial pathogen that causes multiple infections. We report high-depth-coverage RNA-Seq data from three NTHi strains, each of which encodes a different phase-variable methyltransferase.

scholarly journals Pharmacokinetics/Pharmacodynamics of Pulmonary Delivery of Colistin against Pseudomonas aeruginosa in a Mouse Lung Infection Model

2016 ◽  
Vol 61 (3) ◽  
Author(s):  
Yu-Wei Lin ◽  
Qi Tony Zhou ◽  
Soon-Ee Cheah ◽  
Jinxin Zhao ◽  
Ke Chen ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Pulmonary Inflammation ◽  
Pulmonary Delivery ◽  
Lung Infection ◽  
Dose Fractionation ◽  
Antimicrobial Efficacy ◽  
Mouse Lung ◽  
Infection Model ◽  
Content Type ◽  
Intratracheal Delivery

ABSTRACT Colistin is often administered by inhalation and/or the parenteral route for the treatment of respiratory infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa. However, limited pharmacokinetic (PK) and pharmacodynamic (PD) data are available to guide the optimization of dosage regimens of inhaled colistin. In the present study, PK of colistin in epithelial lining fluid (ELF) and plasma was determined following intratracheal delivery of a single dose of colistin solution in neutropenic lung-infected mice. The antimicrobial efficacy of intratracheal delivery of colistin against three P. aeruginosa strains (ATCC 27853, PAO1, and FADDI-PA022; MIC of 1 mg/liter for all strains) was examined in a neutropenic mouse lung infection model. Dose fractionation studies were conducted over 2.64 to 23.8 mg/kg of body weight/day. The inhibitory sigmoid model was employed to determine the PK/PD index that best described the antimicrobial efficacy of pulmonary delivery of colistin. In both ELF and plasma, the ratio of the area under the unbound concentration-time profile to MIC (fAUC/MIC) was the PK/PD index that best described the antimicrobial effect in mouse lung infection (R 2 = 0.60 to 0.84 for ELF and 0.64 to 0.83 for plasma). The fAUC/MIC targets required to achieve stasis against the three strains were 684 to 1,050 in ELF and 2.15 to 3.29 in plasma. The histopathological data showed that pulmonary delivery of colistin reduced infection-caused pulmonary inflammation and preserved the integrity of the lung epithelium, although colistin introduced mild pulmonary inflammation in healthy mice. This study showed pulmonary delivery of colistin provides antimicrobial effects against MDR P. aeruginosa lung infections superior to those of parenteral administrations. For the first time, our results provide important preclinical PK/PD information for optimization of inhaled colistin therapy.

scholarly journals Eravacycline (TP-434) Is Efficacious in Animal Models of Infection

2015 ◽  
Vol 59 (5) ◽  
pp. 2567-2571 ◽  
Author(s):  
Trudy H. Grossman ◽  
Timothy M. Murphy ◽  
Andrew M. Slee ◽  
Denene Lofland ◽  
Joyce A. Sutcliffe
Keyword(s):  
Lung Infection ◽  
Mouse Lung ◽  
Infection Model ◽  
Murine Models ◽  
Bacterial Burden ◽  
Content Type ◽  
E Coli ◽  
Serious Infections ◽  
Infection Models ◽  
Wide Range

ABSTRACTEravacycline is a novel broad-spectrum fluorocycline antibiotic being developed for a wide range of serious infections. Eravacycline was efficacious in mouse septicemia models, demonstrating 50% protective dose (PD50) values of ≤1 mg/kg of body weight once a day (q.d.) againstStaphylococcus aureus, including tetracycline-resistant isolates of methicillin-resistantS. aureus(MRSA), andStreptococcus pyogenes. The PD50values againstEscherichia coliisolates were 1.2 to 4.4 mg/kg q.d. In neutropenic mouse thigh infection models with methicillin-sensitiveS. aureus(MSSA) andS. pyogenes, eravacycline produced 2 log10reductions in CFU at single intravenous (i.v.) doses ranging from 0.2 to 9.5 mg/kg. In a neutropenic mouse lung infection model, eravacycline administered i.v. at 10 mg/kg twice a day (b.i.d.) reduced the level of tetracycline-resistant MRSA in the lung equivalent to that of linezolid given orally (p.o.) at 30 mg/kg b.i.d. At i.v. doses of 3 to 12 mg/kg b.i.d., eravacycline was more efficacious against tetracycline-resistantStreptococcus pneumoniaein a neutropenic lung infection model than linezolid p.o. at 30 mg/kg b.i.d. Eravacycline showed good efficacy at 2 to 10 mg/kg i.v. b.i.d., producing up to a 4.6 log10CFU reduction in kidney bacterial burden in a model challenged with a uropathogenicE. coliisolate. Eravacycline was active in multiple murine models of infection against clinically important Gram-positive and Gram-negative pathogens.

scholarly journals Elucidating the Pharmacokinetics/Pharmacodynamics of Aerosolized Colistin against Multidrug-Resistant Acinetobacter baumannii and Klebsiella pneumoniae in a Mouse Lung Infection Model

2017 ◽  
Vol 62 (2) ◽  
Author(s):  
Yu-Wei Lin ◽  
Qi Tony Zhou ◽  
Mei-Ling Han ◽  
Ke Chen ◽  
Nikolas J. Onufrak ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Acinetobacter Baumannii ◽  
Lung Infection ◽  
Multidrug Resistant ◽  
Dose Fractionation ◽  
Mouse Lung ◽  
Infection Model ◽  
Time Curve ◽  
Epithelial Lining Fluid ◽  
Content Type

ABSTRACT The pharmacokinetics/pharmacodynamics (PK/PD) of aerosolized colistin was investigated against Acinetobacter baumannii and Klebsiella pneumoniae over 24 h in a neutropenic mouse lung infection model. Dose fractionation studies were performed over 2.64 to 23.8 mg/kg/day, and the data were fitted to a sigmoid inhibitory model. The area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC) in the epithelial lining fluid was the most predictive PK/PD index for aerosolized colistin against both pathogens. Our study provides important pharmacological information for optimizing aerosolized colistin.

scholarly journals Requirement of the Pseudomonas aeruginosa CbrA Sensor Kinase for Full Virulence in a Murine Acute Lung Infection Model

2013 ◽  
Vol 82 (3) ◽  
pp. 1256-1267 ◽  
Author(s):  
Amy T. Y. Yeung ◽  
Laure Janot ◽  
Olga M. Pena ◽  
Anke Neidig ◽  
Irena Kukavica-Ibrulj ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Lung Infection ◽  
Lung Model ◽  
Transcriptional Analysis ◽  
Infection Model ◽  
Sensor Kinase ◽  
Wild Type ◽  
Bacterial Killing ◽  
Content Type

ABSTRACTPseudomonas aeruginosais an opportunistic pathogen that is a major cause of respiratory tract and other nosocomial infections. The sensor kinase CbrA is a central regulator of carbon and nitrogen metabolism andin vitroalso regulates virulence-related processes inP. aeruginosa. Here, we investigated the role of CbrA in two murine models of infection. In both peritoneal infections in leukopenic mice and lung infection models, thecbrAmutant was less virulent since substantially larger numbers ofcbrAmutant bacteria were required to cause the same level of infection as wild-type or complemented bacteria. In contrast, in the chronic rat lung model thecbrAmutant grew and persisted as well as the wild type, indicating that the decrease ofin vivovirulence of thecbrAmutant did not result from growth deficiencies on particular carbon substrates observedin vitro. In addition, a mutant in the cognate response regulator CbrB showed no defect in virulence in the peritoneal infection model, ruling out the involvement of certain alterations of virulence properties in thecbrAmutant including defective swarming motility, increased biofilm formation, and cytotoxicity, since these alterations are controlled through CbrB. Further investigations indicated that the mutant was more susceptible to uptake by phagocytesin vitro, resulting in greater overall bacterial killing. Consistent with the virulence defect, it took a smaller number ofDictyostelium discoideumamoebae to kill thecbrAmutant than to kill the wild type. Transcriptional analysis of thecbrAmutant duringD. discoideuminfection led to the conclusion that CbrA played an important role in the iron metabolism, protection ofP. aeruginosaagainst oxidative stress, and the regulation of certain virulence factors.

scholarly journals Activity of Aerosolized Levofloxacin against Burkholderia cepacia in a Mouse Model of Chronic Lung Infection

2019 ◽  
Vol 64 (2) ◽  
Author(s):  
Mojgan Sabet ◽  
David C. Griffith
Keyword(s):  
Burkholderia Cepacia ◽  
Opportunistic Pathogen ◽  
Lung Infection ◽  
Mouse Lung ◽  
Infection Model ◽  
Pulmonary Infections ◽  
Bacterial Killing ◽  
Content Type ◽  
Lung Infections ◽  
Chronic Lung Infection

ABSTRACT Burkholderia cepacia complex is an opportunistic pathogen capable of causing chronic pulmonary infections. These studies were conducted to demonstrate the activity of aerosolized levofloxacin in a chronic mouse lung infection model caused by B. cepacia isolates from patients with cystic fibrosis. Treatment with aerosolized levofloxacin for 4 days produced at least 1 log CFU of bacterial killing against all strains tested, suggesting possible utility in the treatment of lung infections caused by B. cepacia isolates.

scholarly journals Efficacy of a Conjugate Vaccine Containing Polymannuronic Acid and Flagellin against Experimental Pseudomonas aeruginosa Lung Infection in Mice

2011 ◽  
Vol 79 (8) ◽  
pp. 3455-3464 ◽  
Author(s):  
Victoria L. Campodónico ◽  
Nicolas J. Llosa ◽  
Leticia V. Bentancor ◽  
Tomas Maira-Litran ◽  
Gerald B. Pier
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Conjugate Vaccine ◽  
Protective Efficacy ◽  
Lung Infection ◽  
Microbial Pathogens ◽  
Mouse Lung ◽  
Infection Model ◽  
Content Type ◽  
Flagellar Proteins ◽  
Toll Like Receptor 5

ABSTRACTVaccines that could effectively preventPseudomonas aeruginosapulmonary infections in the settings of cystic fibrosis (CF) and nosocomial pneumonia could be exceedingly useful, but to date no effective immunotherapy targeting this pathogen has been successfully developed for routine use in humans. Evaluations using animals and limited human trials of vaccines and their associated immune effectors against differentP. aeruginosaantigens have suggested that antibody to the conserved surface polysaccharide alginate, as well as the flagellar proteins, often give high levels of protection. However, alginate itself does not elicit protective antibody in humans, and flagellar vaccines containing the two predominant serotypes of this antigen may not provide sufficient coverage against variant flagellar types. To evaluate if combining these antigens in a conjugate vaccine would be potentially efficacious, we conjugated polymannuronic acid (PMA), containing the blocks of mannuronic acid conserved in allP. aeruginosaalginates, to type a flagellin (FLA) and evaluated immunogenicity, opsonic killing activity, and passive protective efficacy in mice. The PMA-FLA conjugate was highly immunogenic in mice and rabbits and elicited opsonic antibodies against mucoid but not nonmucoidP. aeruginosa, but nonetheless rabbit antibody to PMA-FLA showed evidence of protective efficacy against both types of this organism in a mouse lung infection model. Importantly, the PMA-FLA conjugate vaccine did not elicit antibodies that neutralized the Toll-like receptor 5 (TLR5)-activating activity of flagellin, an important part of innate immunity to flagellated microbial pathogens. Conjugation of PMA to FLA appears to be a promising path for developing a broadly protective vaccine againstP. aeruginosa.

Nontypeable Haemophilus influenzae infection impedes Pseudomonas aeruginosa colonization and persistence in mouse respiratory tract

2021 ◽  
Author(s):  
Natalie Lindgren ◽  
Lea Novak ◽  
Benjamin C. Hunt ◽  
Melissa S. McDaniel ◽  
W. Edward Swords
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Respiratory Tract ◽  
Haemophilus Influenzae ◽  
Respiratory Infections ◽  
Bacterial Species ◽  
Young Patients ◽  
Nontypeable Haemophilus Influenzae ◽  
Potential Significance ◽  
And Diffusion

Patients with cystic fibrosis (CF) experience lifelong respiratory infections which are a significant cause of morbidity and mortality. These infections are polymicrobial in nature, and the predominant bacterial species undergo a predictable series of changes as patients age. Young patients have populations dominated by opportunists that are typically found within the microbiome of the human nasopharynx, such as nontypeable Haemophilus influenzae (NTHi); these are eventually supplanted and the population within the CF lung is later dominated by pathogens such as Pseudomonas aeruginosa ( Pa ). In this study, we investigated how initial colonization with NTHi impacts colonization and persistence of Pa in the respiratory tract. Analysis of polymicrobial biofilms in vitro by confocal microscopy revealed that NTHi promoted greater levels of Pa biofilm volume and diffusion. However, sequential respiratory infection of mice with NTHi followed by Pa resulted in significantly lower Pa as compared to infection with Pa alone. Coinfected mice also had reduced airway tissue damage and lower levels of inflammatory cytokines as compared with Pa infected mice. Similar results were observed after instillation of heat-inactivated NTHi bacteria or purified NTHi lipooligosaccharide (LOS) endotoxin prior to Pa introduction. Based on these results, we conclude that NTHi significantly reduces susceptibility to subsequent Pa infection, most likely due to priming of host innate immunity rather than a direct competitive interaction between species. These findings have potential significance with regard to therapeutic management of early life infections in patients with CF.

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