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BMC Veterinary Research Apr 2024Gamithromycin is an effective therapy for bovine and swine respiratory diseases but not utilized for rabbits. Given its potent activity against respiratory pathogens, we...
BACKGROUND
Gamithromycin is an effective therapy for bovine and swine respiratory diseases but not utilized for rabbits. Given its potent activity against respiratory pathogens, we sought to determine the pharmacokinetic profiles, antimicrobial activity and target pharmacokinetic/pharmacodynamic (PK/PD) exposures associated with therapeutic effect of gamithromycin against Pasteurella multocida in rabbits.
RESULTS
Gamithromycin showed favorable PK properties in rabbits, including high subcutaneous bioavailability (86.7 ± 10.7%) and low plasma protein binding (18.5-31.9%). PK analysis identified a mean plasma peak concentration (C) of 1.64 ± 0.86 mg/L and terminal half-life (T) of 31.5 ± 5.74 h after subcutaneous injection. For P. multocida, short post-antibiotic effects (PAE) (1.1-5.3 h) and post-antibiotic sub-inhibitory concentration effects (PA-SME) (6.6-9.1 h) were observed after exposure to gamithromycin at 1 to 4× minimal inhibitory concentration (MIC). Gamithromycin demonstrated concentration-dependent bactericidal activity and the PK/PD index area under the concentration-time curve over 24 h (AUC)/MIC correlated well with efficacy (R > 0.99). The plasma AUC/MIC ratios of gamithromycin associated with the bacteriostatic, bactericidal and bacterial eradication against P. multocida were 15.4, 24.9 and 27.8 h in rabbits, respectively.
CONCLUSIONS
Subcutaneous administration of 6 mg/kg gamithromycin reached therapeutic concentrations in rabbit plasma against P. multocida. The PK/PD ratios determined herein in combination with ex vivo activity and favorable rabbit PK indicate that gamithromycin may be used for the treatment of rabbit pasteurellosis.
Topics: Rabbits; Animals; Cattle; Swine; Anti-Bacterial Agents; Pasteurella Infections; Macrolides; Pasteurella multocida; Lagomorpha; Microbial Sensitivity Tests; Cattle Diseases; Swine Diseases
PubMed: 38643185
DOI: 10.1186/s12917-024-03988-y -
Revista Espanola de Quimioterapia :... Jun 2024
Topics: Animals; Humans; Male; Anti-Bacterial Agents; Arthritis, Infectious; Pasteurella Infections; Pasteurella multocida; Middle Aged
PubMed: 38627987
DOI: 10.37201/req/019.2024 -
Internal Medicine (Tokyo, Japan) Apr 2024
PubMed: 38599860
DOI: 10.2169/internalmedicine.3576-24 -
Veterinary Research Apr 2024Pasteurella multocida is an important zoonotic respiratory pathogen capable of infecting a diverse range of hosts, including humans, farm animals, and wild animals....
Pasteurella multocida is an important zoonotic respiratory pathogen capable of infecting a diverse range of hosts, including humans, farm animals, and wild animals. However, the precise mechanisms by which P. multocida compromises the pulmonary integrity of mammals and subsequently induces systemic infection remain largely unexplored. In this study, based on mouse and rabbit models, we found that P. multocida causes not only lung damage but also bacteremia due to the loss of lung integrity. Furthermore, we demonstrated that bacteremia is an important aspect of P. multocida pathogenesis, as evidenced by the observed multiorgan damage and systemic inflammation, and ultimately found that this systemic infection leads to a cytokine storm that can be mitigated by IL-6-neutralizing antibodies. As a result, we divided the pathogenesis of P. multocida into two phases: the pulmonary infection phase and the systemic infection phase. Based on unbiased RNA-seq data, we discovered that P. multocida-induced apoptosis leads to the loss of pulmonary epithelial integrity. These findings have been validated in both TC-1 murine lung epithelial cells and the lungs of model mice. Conversely, the administration of Ac-DEVD-CHO, an apoptosis inhibitor, effectively restored pulmonary epithelial integrity, significantly mitigated lung damage, inhibited bacteremia, attenuated the cytokine storm, and reduced mortality in mouse models. At the molecular level, we demonstrated that the FAK-AKT-FOXO1 axis is involved in P. multocida-induced lung epithelial cell apoptosis in both cells and animals. Thus, our research provides crucial information with regard to the pathogenesis of P. multocida as well as potential treatment options for this and other respiratory bacterial diseases.
Topics: Humans; Animals; Rabbits; Mice; Pasteurella multocida; Pasteurella Infections; Proto-Oncogene Proteins c-akt; Cytokine Release Syndrome; Lung; Bacteremia; Apoptosis; Mammals; Forkhead Box Protein O1; Rodent Diseases
PubMed: 38589976
DOI: 10.1186/s13567-024-01298-7 -
Open Life Sciences 2024Bovine respiratory disease (BRD) is a significant veterinary challenge, often exacerbated by pathogen resistance, hindering effective treatment. Traditional testing...
Bovine respiratory disease (BRD) is a significant veterinary challenge, often exacerbated by pathogen resistance, hindering effective treatment. Traditional testing methods for primary pathogens - , , and - are notably time-consuming and lack the rapidity required for effective clinical decision-making. This study introduces a TaqMan MGB probe detection chip, utilizing fluorescent quantitative PCR, targeting key BRD pathogens and associated drug-resistant genes and sites. We developed 94 specific probes and primers, embedded into a detection chip, demonstrating notable specificity, repeatability, and sensitivity, reducing testing time to under 1 h. Additionally, we formulated probes to detect mutations in the quinolone resistance-determining region, associated with fluoroquinolone resistance in BRD pathogens. The chip exhibited robust sensitivity and specificity, enabling rapid detection of drug-resistant mutations in clinical samples. This methodology significantly expedites the diagnostic process for BRD and sensitive drug screening, presenting a practical advancement in the field.
PubMed: 38585641
DOI: 10.1515/biol-2022-0778 -
Vaccine Apr 2024As the major outer membrane protein (OMP) presents in the Pasteurella multocida envelope, OmpH was frequently expressed for laboratory assessments of its immunogenicity...
Dendritic cell targeting peptide plus Salmonella FliCd flagellin fused outer membrane protein H (OmpH) demonstrated increased efficacy against infections caused by different Pasteurella multocida serogroups in mouse models.
As the major outer membrane protein (OMP) presents in the Pasteurella multocida envelope, OmpH was frequently expressed for laboratory assessments of its immunogenicity against P. multocida infections, but the results are not good. In this study, we modified OmpH with dendritic cell targeting peptide (Depeps) and/or Salmonella FliCd flagellin, and expressed three types of recombinant proteins with the MBP tag (rDepeps-FliC-OmpH-MBP, rDepeps-OmpH-MBP, rFliC-OmpH-MBP). Assessments in mouse models revealed that vaccination with rDepeps-FliC-OmpH-MBP, rDepeps-OmpH-MBP, or rFliC-OmpH-MBP induced significant higher level of antibodies as well as IFN-γ and IL-4 in murine sera than vaccination with rOmpH-MBP (P < 0.5). Vaccination with the three modified proteins also provided increased protection (rDepeps-FliC-OmpH-MBP, 70 %; rDepeps-OmpH-MBP, 50 %; rFliC-OmpH-MBP, 60 %) against P. multocida serotype D compared to vaccination with rOmpH-MBP (30 %). In mice vaccinated with different types of modified OmpHs, a significantly decreased bacterial strains were recovered from bloods, lungs, and spleens compared to rOmpH-MBP-vaccinated mice (P < 0.5). Notably, our assessments also demonstrated that vaccination with rDepeps-FliC-OmpH-MBP provided good protection against infections caused by a heterogeneous group of P. multocida serotypes (A, B, D). Our above findings indicate that modification with DCpep and Salmonella flagellin could be used as a promising strategy to improve vaccine effectiveness.
Topics: Animals; Mice; Pasteurella multocida; Serogroup; Pasteurella Infections; Flagellin; Bacterial Outer Membrane Proteins; Peptides; Dendritic Cells; Bacterial Vaccines
PubMed: 38584060
DOI: 10.1016/j.vaccine.2024.04.020 -
Journal of Orthopaedic Case Reports Mar 2024Prosthetic joint infections (PJIs) are a dreaded complication of joint arthroplasty. Zoonotic organisms such as Pasteurella multocida (PM) rarely cause PJIs. Still,...
INTRODUCTION
Prosthetic joint infections (PJIs) are a dreaded complication of joint arthroplasty. Zoonotic organisms such as Pasteurella multocida (PM) rarely cause PJIs. Still, these organisms can be challenging to treat due to a low suspicion index and inadequate growth on culture. Next-generation sequencing (NGS) can be used to identify organisms in culture-negative PJIs. This is the first reported case of a PM positive total hip arthroplasty PJI using NGS.
CASE REPORT
We report the case of a 70-year-old male presenting with a periprosthetic hip infection. PM was identified in high relative abundance on NGS and grew in culture. Subsequent intraoperative samples were culture negative for Pasteurella, but NGS demonstrated continued presence of Pasteurella.
CONCLUSION
PM is a rare case of PJI, but a high index of suspicion must be maintained in the appropriate clinical context. NGS is a vital tool for the identification of culture-negative organisms like PM.
PubMed: 38560323
DOI: 10.13107/jocr.2024.v14.i03.4284 -
Applied and Environmental Microbiology Apr 2024is a zoonotic conditional pathogen that infects multiple livestock species, causing substantial economic losses in the animal husbandry industry. An efficient...
is a zoonotic conditional pathogen that infects multiple livestock species, causing substantial economic losses in the animal husbandry industry. An efficient markerless method for gene manipulation may facilitate the investigations of gene function and pathogenesis of . Herein, a temperature-sensitive shuttle vector was constructed using as a selection marker, and markerless , , and mutants of were subsequently constructed through blue-white colony screening. The screening efficiency of markerless deletion strains was improved by the system, and the method could be used for multiple gene deletions. However, the mutant was unavailable via this method. Therefore, we constructed a m screening system based on mutated phenylalanine tRNA synthetase as a counterselection marker to achieve deletion mutant. The transformed strain was sensitive to 20 mM -chloro-phenylalanine, demonstrating the feasibility of m as a counter-selective marker. The m system was used for markerless deletions of , , and as well as that could not be screened by the system. A comparison of screening efficiencies of the system showed that the m counterselection system was more efficient than the system and broadly applicable for mutant screening. The methods developed herein may provide valuable tools for genetic manipulation of .IMPORTANCE is a highly contagious zoonotic pathogen. An understanding of its underlying pathogenic mechanisms is of considerable importance and requires efficient species-specific genetic tools. Herein, we propose a screening system for mutants using or m screening markers. We evaluated the efficiencies of both systems, which were used to achieve markerless deletion of multiple genes. The results of this study support the use of or m as counterselection markers to improve counterselection efficiency in . This study provides an effective genetic tool for investigations of the virulence gene functions and pathogenic mechanisms of .
Topics: Animals; Pasteurella multocida; Lac Operon; Genetic Vectors; Phenylalanine
PubMed: 38547470
DOI: 10.1128/aem.02043-23 -
Microbial Genomics Mar 2024With emerging infectious disease outbreaks in human, domestic and wild animal populations on the rise, improvements in pathogen characterization and surveillance are...
With emerging infectious disease outbreaks in human, domestic and wild animal populations on the rise, improvements in pathogen characterization and surveillance are paramount for the protection of human and animal health, as well as the conservation of ecologically and economically important wildlife. Genomics offers a range of suitable tools to meet these goals, with metagenomic sequencing facilitating the characterization of whole microbial communities associated with emerging and endemic disease outbreaks. Here, we use metagenomic sequencing in a case-control study to identify microbes in lung tissue associated with newly observed pneumonia-related fatalities in 34 white-tailed deer () in Wisconsin, USA. We identified 20 bacterial species that occurred in more than a single individual. Of these, only was found to substantially differ (in number of detections) between case and control sample groups; however, this difference was not statistically significant. We also detected several bacterial species associated with pneumonia and/or other diseases in ruminants (, , , , ); however, these species did not substantially differ between case and control sample groups. On average, we detected a larger number of bacterial species in case samples than controls, supporting the potential role of polymicrobial infections in this system. Importantly, we did not detect DNA of viruses or fungi, suggesting that they are not significantly associated with pneumonia in this system. Together, these results highlight the utility of metagenomic sequencing for identifying disease-associated microbes. This preliminary list of microbes will help inform future research on pneumonia-associated fatalities of white-tailed deer.
Topics: Animals; Humans; Deer; Case-Control Studies; Pneumonia; Metagenomics; Animals, Wild
PubMed: 38536208
DOI: 10.1099/mgen.0.001214 -
Journal of Dairy Science Mar 2024This study investigated the potential associations between 3 acute phase proteins (APPs) haptoglobin, serum amyloid A, and fibrinogen, clinical signs of respiratory...
This study investigated the potential associations between 3 acute phase proteins (APPs) haptoglobin, serum amyloid A, and fibrinogen, clinical signs of respiratory disease, and the presence of bacterial pathogens in the lower respiratory tract (LRT) of pre-weaned dairy calves. This cross-sectional study included 150 pre-weaned calves (2-86 d old) from 15 large dairy herds in Estonia. Tracheobronchial lavage, blood, and fecal samples were collected from 5 calves showing clinical signs indicative of LRT disease, and samples from 5 calves without clinical signs of LRT disease per herd. All samples collected from these calves were analyzed for concentrations of systemic APPs, LRT bacteria, and intestinal pathogens. Heifer blood and bulk tank milk samples were collected for the detection of disease-specific antibodies against bovine herpesvirus 1, bovine viral diarrhea virus, bovine respiratory syncytial virus, and Mycoplasma bovis. Mixed-effects linear regression models were used to analyze the associations of clinical respiratory disease signs and LRT bacteria with APPs. Increased plasma fibrinogen concentrations in calves were associated with higher rectal temperature (>39.5°C), increased respiratory rate (>50 breaths/min), and coughing. Increased serum amyloid A concentrations were associated with higher rectal temperature (>39.5°C) and respiratory rate between 40 and 50 breaths/min. Calves with the presence of fecal Cryptosporidium spp. and rectal temperature of 39°C and above had increased serum haptoglobin concentrations. Increased fibrinogen concentrations were associated with the presence of Pasteurella multocida in the calf LRT, whereas increased concentrations of fibrinogen and serum amyloid A were associated with the presence of Trueperella pyogenes. In conclusion, APPs showed variable associations with clinical signs of respiratory disease and LRT bacteria. Plasma fibrinogen concentration could be used as a complementary calf-side test to assess systemic inflammation caused by LRT bacteria such as P. multocida and T. pyogenes in pre-weaned dairy calves.
PubMed: 38522828
DOI: 10.3168/jds.2023-24084