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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 -
Respiratory Research Apr 2024Our understanding of airway dysbiosis in chronic obstructive pulmonary disease (COPD) remains incomplete, which may be improved by unraveling the complexity in microbial...
RATIONALE
Our understanding of airway dysbiosis in chronic obstructive pulmonary disease (COPD) remains incomplete, which may be improved by unraveling the complexity in microbial interactome.
OBJECTIVES
To characterize reproducible features of airway bacterial interactome in COPD at clinical stability and during exacerbation, and evaluate their associations with disease phenotypes.
METHODS
We performed weighted ensemble-based co-occurrence network analysis of 1742 sputum microbiomes from published and new microbiome datasets, comprising two case-control studies of stable COPD versus healthy control, two studies of COPD stability versus exacerbation, and one study with exacerbation-recovery time series data.
RESULTS
Patients with COPD had reproducibly lower degree of negative bacterial interactions, i.e. total number of negative interactions as a proportion of total interactions, in their airway microbiome compared with healthy controls. Evaluation of the Haemophilus interactome showed that the antagonistic interaction networks of this established pathogen rather than its abundance consistently changed in COPD. Interactome dynamic analysis revealed reproducibly reduced antagonistic interactions but not diversity loss during COPD exacerbation, which recovered after treatment. In phenotypic analysis, unsupervised network clustering showed that loss of antagonistic interactions was associated with worse clinical symptoms (dyspnea), poorer lung function, exaggerated neutrophilic inflammation, and higher exacerbation risk. Furthermore, the frequent exacerbators (≥ 2 exacerbations per year) had significantly reduced antagonistic bacterial interactions while exhibiting subtle compositional changes in their airway microbiota.
CONCLUSIONS
Bacterial interactome disturbance characterized by reduced antagonistic interactions, rather than change in pathogen abundance or diversity, is a reproducible feature of airway dysbiosis in COPD clinical stability and exacerbations, which suggests that we may target interactome rather than pathogen alone for disease treatment.
Topics: Humans; Dysbiosis; Pulmonary Disease, Chronic Obstructive; Lung; Haemophilus; Sputum; Disease Progression
PubMed: 38643126
DOI: 10.1186/s12931-024-02802-5 -
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 -
BMJ Case Reports Apr 2024Infective endocarditis (IE) caused by is a rare but serious condition if not diagnosed and treated promptly. In this article, we describe a patient with IE who...
Infective endocarditis (IE) caused by is a rare but serious condition if not diagnosed and treated promptly. In this article, we describe a patient with IE who initially presented with non-specific symptoms but subsequently developed multiple sequelae of IE. The diagnosis of IE was made based on clinical, echocardiographic, radiological and microbiological findings. He was treated successfully with a mitral valve replacement along with 4 weeks of intravenous antibiotic therapy. Our case highlights the importance of obtaining a thorough history and a complete physical examination to ensure an early diagnosis of IE.
Topics: Male; Humans; Haemophilus parainfluenzae; Haemophilus Infections; Endocarditis, Bacterial; Endocarditis; Echocardiography
PubMed: 38627050
DOI: 10.1136/bcr-2023-256308 -
Human Vaccines & Immunotherapeutics Dec 2024DTaP-HBV-IPV-Hib hexavalent vaccine has been used in high-income countries for many years to prevent diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis, and...
DTaP-HBV-IPV-Hib hexavalent vaccine has been used in high-income countries for many years to prevent diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis, and invasive Haemophilus influenzae type b disease. Currently, no hexavalent vaccines have been approved for use in China. Evidence of parental acceptance and interest in hexavalent vaccines can help policy makers and manufacturers make decisions about entering the vaccine market and the immunization program in China. We measured parental acceptance and willingness-to-pay (WTP) for a hexavalent vaccine to provide such evidence. We conducted a cross-sectional survey of children's caregivers in 16 vaccination clinics in seven cities in China and obtained information on socio-demographics, knowledge of disease, confidence in vaccines, previous vaccination experience, and acceptance of and WTP for hexavalent vaccine. Multivariate logistic regression was used to determine factors influencing acceptance, and multivariate tobit regression was used to identify factors impacting WTP. Between April 28 and June 30, 2023, a total of 581 parents of children aged 0-6 years participated in the survey; 435 (74.87%, 95% CI:71.3%-78.4%) parents indicated acceptance of hexavalent vaccine. Residence location, parents' education level, experience paying for vaccination, and disease knowledge scores were key factors affecting parents' choices for vaccination. Mean (SD) and median (IQR) willingness to pay for full 4-dose course vaccination were 2266.66 (1177.1) CNY and 2400 (1600-2800) CNY. Children's age ( < .001), parents' education level ( = .024), and perceived price barriers ( < .001) were significantly associated with WTP. Parents have high acceptance and willingness to pay for hexavalent vaccine. The less money parents have to pay out of pocket, the more willing they can be to accept the vaccine. Therefore, acceptance may increase even further if the vaccine is covered by medical insurance, provided free of charge by the government, or if its price is reduced. Our results provide reference for optimizing and adjusting immunization strategies in China.
Topics: Child; Humans; Vaccines, Combined; Cross-Sectional Studies; Haemophilus influenzae type b; China; Diphtheria-Tetanus-Pertussis Vaccine; Hepatitis B Vaccines; Haemophilus Vaccines
PubMed: 38619056
DOI: 10.1080/21645515.2024.2333098 -
Infection and Immunity May 2024Nontypeable (NTHi) is a major otitis media (OM) pathogen, with colonization a prerequisite for disease development. Most acute OM is in children <5 years old, with...
Nontypeable (NTHi) is a major otitis media (OM) pathogen, with colonization a prerequisite for disease development. Most acute OM is in children <5 years old, with recurrent and chronic OM impacting hearing and learning. Therapies to prevent NTHi colonization and/or disease are needed, especially for young children. Respiratory viruses are implicated in driving the development of bacterial OM in children. We have developed an infant mouse model of influenza-driven NTHi OM, as a preclinical tool for the evaluation of safety and efficacy of clinical therapies to prevent NTHi colonization and the development of OM. In this model, 100% of infant BALB/cARC mice were colonized with NTHi, and all developed NTHi OM. Influenza A virus (IAV) facilitated the establishment of dense (1 × 10 CFU/mL) and long-lasting (6 days) NTHi colonization. IAV was essential for the development of NTHi OM, with 100% of mice in the IAV/NTHi group developing NTHi OM compared with 8% of mice in the NTHi only group. Histological analysis and cytokine measurements revealed that the inflammation observed in the middle ear of the infant mice with OM reflected inflammation observed in children with OM. We have developed the first infant mouse model of NTHi colonization and OM. This ascension model uses influenza-driven establishment of OM and reflects the clinical pathology of bacterial OM developing after a respiratory virus infection. This model provides a valuable tool for testing therapies to prevent or treat NTHi colonization and disease in young children.
Topics: Animals; Otitis Media; Haemophilus influenzae; Haemophilus Infections; Disease Models, Animal; Mice; Influenza A virus; Mice, Inbred BALB C; Orthomyxoviridae Infections; Humans; Animals, Newborn
PubMed: 38602405
DOI: 10.1128/iai.00453-23 -
Frontiers in Cellular and Infection... 2024The Gram-positive bacterium, is an oral pathogen, and approximately 50% of known strains encode a recently identified repeat-in-toxin (RTX) protein, FtxA. By assessing...
The Gram-positive bacterium, is an oral pathogen, and approximately 50% of known strains encode a recently identified repeat-in-toxin (RTX) protein, FtxA. By assessing a longitudinal Ghanaian study population of adolescents (10-19 years of age; mean age 13.2 years), we recently discovered a possible correlation between deep periodontal pockets measured at the two-year follow-up, presence of the gene, and a high quantity of . To further understand the contribution of and FtxA in periodontal disease, we used qPCR in the present study to assess the carriage loads of and the prevalence of its gene in subgingival plaque specimens, sampled at baseline from the Ghanaian cohort (n=500). Comparing these results with the recorded clinical attachment loss (CAL) longitudinal progression data from the two-year follow up, we concluded that carriers of -positive typically exhibited higher loads of the bacterium. Moreover, high carriage loads of and concomitant presence of the gene were two factors that were both associated with an enhanced prevalence of CAL progression. Interestingly, CAL progression appeared to be further promoted upon the simultaneous presence of and the non-JP2 genotype of . Taken together, our present findings are consistent with the notion that and its gene promotes CAL during periodontal disease.
Topics: Adolescent; Humans; Aggregatibacter actinomycetemcomitans; Periodontal Attachment Loss; Ghana; Periodontal Diseases; Toxins, Biological; Clostridiales
PubMed: 38596650
DOI: 10.3389/fcimb.2024.1376358 -
Veterinary Research Apr 2024Actinobacillus pleuropneumoniae (APP) is a bacterium frequently associated with porcine pleuropneumonia. The acute form of the disease is highly contagious and often...
Actinobacillus pleuropneumoniae (APP) is a bacterium frequently associated with porcine pleuropneumonia. The acute form of the disease is highly contagious and often fatal, resulting in significant economic losses for pig farmers. Serotype diversity and antimicrobial resistance (AMR) of APP strains circulating in north Italian farms from 2015 to 2022 were evaluated retrospectively to investigate APP epidemiology in the area. A total of 572 strains isolated from outbreaks occurring in 337 different swine farms were analysed. The majority of isolates belonged to serotypes 9/11 (39.2%) and 2 (28.1%) and serotype diversity increased during the study period, up to nine different serotypes isolated in 2022. The most common resistances were against tetracycline (53% of isolates) and ampicillin (33%), followed by enrofloxacin, florfenicol and trimethoprim/sulfamethoxazole (23% each). Multidrug resistance (MDR) was common, with a third of isolates showing resistance to more than three antimicrobial classes. Resistance to the different classes and MDR varied significantly depending on the serotype. In particular, the widespread serotype 9/11 was strongly associated with florfenicol and enrofloxacin resistance and showed the highest proportion of MDR isolates. Serotype 5, although less common, showed instead a concerning proportion of trimethoprim/sulfamethoxazole resistance. Our results highlight how the typing of circulating serotypes and the analysis of their antimicrobial susceptibility profile are crucial to effectively manage APP infection and improve antimicrobial stewardship.
Topics: Swine; Animals; Serogroup; Actinobacillus pleuropneumoniae; Microbial Sensitivity Tests; Enrofloxacin; Farms; Retrospective Studies; Pleuropneumonia; Anti-Bacterial Agents; Sulfamethoxazole; Trimethoprim; Italy; Swine Diseases; Actinobacillus Infections; Serotyping; Thiamphenicol
PubMed: 38594744
DOI: 10.1186/s13567-024-01305-x -
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 -
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