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 Activity of Meropenem-Vaborbactam in Mouse Models of Infection Due to KPC-Producing Carbapenem-Resistant Enterobacteriaceae

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Mojgan Sabet ◽  
Ziad Tarazi ◽  
Thomas Nolan ◽  
Jonathan Parkinson ◽  
Debora Rubio-Aparicio ◽  
...  
Keyword(s):  
Body Weight ◽  
Lung Infection ◽  
Infection Model ◽  
Bacterial Killing ◽  
Gram Negative ◽  
Content Type ◽  
Highly Active ◽  
Carbapenem Resistant ◽  
Infection Models ◽  
Carbapenem Resistant Enterobacteriaceae

ABSTRACT Meropenem-vaborbactam (Vabomere) is highly active against Gram-negative pathogens, especially Klebsiella pneumoniae carbapenemase (KPC)-producing, carbapenem-resistant Enterobacteriaceae. The objective of these studies was to evaluate the efficacy of meropenem alone and in combination with vaborbactam in mouse thigh and lung infection models. Thighs or lungs of neutropenic mice were infected with KPC-producing carbapenem-resistant Enterobacteriaceae, with meropenem MICs ranging from ≤0.06 to 8 mg/liter in the presence of 8 mg/liter vaborbactam. Mice were treated with meropenem alone or meropenem in combination with vaborbactam every 2 h for 24 h to provide exposures comparable to 2-g doses of each component in humans. Meropenem administered in combination with vaborbactam produced bacterial killing in all strains tested, while treatment with meropenem alone either produced less than 0.5 log CFU/tissue of bacterial killing or none at all. In the thigh model, 11 strains were treated with the combination of meropenem plus vaborbactam (300 plus 50 mg/kg of body weight). This combination produced from 0.8 to 2.89 logs of bacterial killing compared to untreated controls at the start of treatment. In the lung infection model, two strains were treated with the same dosage regimen of meropenem and vaborbactam. The combination produced more than 1.83 logs of bacterial killing against both strains tested compared to untreated controls at the start of treatment. Overall, these data suggest that meropenem-vaborbactam may have utility in the treatment of infections due to KPC-producing carbapenem-resistant Enterobacteriaceae.

scholarly journals Comparative Analysis of Plant and Animal Models for Characterization of Burkholderia cepacia Virulence

2003 ◽  
Vol 71 (9) ◽  
pp. 5306-5313 ◽  
Author(s):  
Steve P. Bernier ◽  
Laura Silo-Suh ◽  
Donald E. Woods ◽  
Dennis E. Ohman ◽  
Pamela A. Sokol
Keyword(s):  
Comparative Analysis ◽  
Animal Models ◽  
Burkholderia Cepacia ◽  
Parent Strain ◽  
Lung Infection ◽  
Infection Model ◽  
Burkholderia Multivorans ◽  
Lung Infections

ABSTRACT A simple alfalfa model was developed as an alternative infection model for virulence studies of the Burkholderia cepacia complex. Symptoms of disease were observed in wounded alfalfa seedlings within 7 days following inoculation of 101 to 105 CFU of most strains of the B. cepacia complex. Strains from seven genomovars of the B. cepacia complex were tested for virulence in the alfalfa model, and the degree of virulence was generally similar in strains belonging to the same genomovar. Strains of Burkholderia multivorans and some strains of Burkholderia stabilis did not cause symptoms of disease in alfalfa seedlings. Representative strains were also tested for virulence using the rat agar bead model. Most of the strains tested were able to establish chronic lung infections; B. stabilis strains were the exception. Most of the strains that were virulent in the alfalfa infection model were also virulent in the lung infection model. The B. cepacia genomovar III mutants K56pvdA::tp and K56-H15 were significantly less virulent in the alfalfa infection model than their parent strain. Therefore, this alfalfa infection model may be a useful tool for assessing virulence of strains of the B. cepacia complex and identifying new virulence-associated genes.

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 Draft Genome Sequence for Pseudomonas aeruginosa Strain PAO579, a Mucoid Derivative of PAO381

2012 ◽  
Vol 194 (23) ◽  
pp. 6617-6617 ◽  
Author(s):  
T. Ryan Withers ◽  
Shannon L. Johnson ◽  
Hongwei D. Yu
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Genome Sequence ◽  
Draft Genome ◽  
Opportunistic Pathogen ◽  
Lung Infection ◽  
Draft Genome Sequence ◽  
Content Type ◽  
Chronic Lung Infection

ABSTRACTPseudomonas aeruginosais an opportunistic pathogen that establishes a chronic lung infection in individuals afflicted with cystic fibrosis. Here, we announce the draft genome ofP. aeruginosastrain PAO579, an alginate-overproducing derivative of strain PAO381.

scholarly journals Efficacy of Aerosolized Rifaximin versus Tobramycin for Treatment ofPseudomonas aeruginosaPneumonia in Mice

2019 ◽  
Vol 63 (7) ◽  
Author(s):  
Brandon D. Kirby ◽  
Roy Al Ahmar ◽  
T. Ryan Withers ◽  
Meagan E. Valentine ◽  
Monica Valentovic ◽  
...  
Keyword(s):  
Bacterial Species ◽  
Inhalation Therapy ◽  
Mouse Lung ◽  
Infection Model ◽  
Content Type ◽  
Dose Treatment ◽  
Alginate Production ◽  
Lung Infections

ABSTRACTPseudomonas aeruginosais a Gram-negative opportunistic bacterial pathogen that can cause chronic lung infections in patients with cystic fibrosis (CF). The current preferred treatment for CF lung infections includes inhaled tobramycin (TOB); however, studies suggest TOB cannot effectively inhibit biofilm formation. Using an NIH small compounds drug library approved for safe use in humans, we identified rifaximin (RFX), a semisynthetic, rifamycin family, nonsystemic antibiotic that inhibits alginate production and growth inP. aeruginosa. Inhibition of alginate production was further analyzed using the uronic acid carbazole assay and a promoter reporter assay that measures the transcription of the alginate biosynthetic operon. Compared to TOB, RFX significantly reduced alginate production in laboratory and CF sputum isolates ofP. aeruginosa. In addition, RFX showed a narrow range of MICs when measured with multidrug-resistant bacterial species of clinical relevance, synergistic activities with TOB or amikacin against clinical isolates, as well as reduction towardin vitropreformed biofilms. In C57BL/6 mice, penetration of nebulized TOB into the lungs was shown at a higher level than that of RFX. Further,in vivoassessment using a DBA/2 mouse lung infection model found increased survival rates with a single-dose treatment of nebulized RFX and decreasedP. aeruginosaPAO1 bioburden with a multiple-dose treatment of RFX plus TOB. In addition, mice treated with a single exposure to dimethyl sulfoxide (DMSO), a solvent that dissolves RFX, showed no apparent toxicity. In summary, RFX may be used to supplement TOB inhalation therapy to increase efficacy againstP. aeruginosabiofilm infections.

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 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.

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