Tulathromycin Exerts Proresolving Effects in Bovine Neutrophils by Inhibiting Phospholipases and Altering Leukotriene B4, Prostaglandin E2, and Lipoxin A4Production

Fischer, Carrie D.; Duquette, Stephanie; Renaux, Bernard; Feener, Troy; Morck, Douglas W.; Hollenberg, Morley D.; Lucas, Merlyn J.; Buret, André G.

doi:10.1128/aac.02813-14

Cited by 17 publications

(24 citation statements)

References 57 publications

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“…This is further evidence of a possible disconnect between in vitro testing results and treatment outcome, especially as it pertains to the macrolide class of antimicrobials, as has been previously reported (Amsden, 2001;Kanoh and Rubin, 2010;McClary et al, 2011 (Amsden, 2005;Kanoh and Rubin, 2010). While no such data are available on gamithromycin, another veterinary macrolide has been extensively studied in this area (Duquette et al, 2015;Er and Yazar, 2012;Fischer et al, 2013;Fischer et al, 2011;Fischer et al, 2014). Additionally, azithromycin, a macrolide of the same subclass as gamithromycin, has been shown to exert anti-inflammatory properties on lung epithelial cells in humans (Kitsiouli et al, 2015).…”

Section: Discussionmentioning

confidence: 87%

Observations on macrolide resistance and susceptibility testing performance in field isolates collected from clinical bovine respiratory disease cases

DeDonder

Harhay

Apley

et al. 2016

Veterinary Microbiology

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The objectives of this study were; first, to describe gamithromycin susceptibility of Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni isolated from cattle diagnosed with bovine respiratory disease (BRD) and previously treated with either gamithromycin for control of BRD (mass medication=MM) or sham-saline injected (control=CON); second, to describe the macrolide resistance genes present in genetically typed M. haemolytica isolates; third, use whole-genome sequencing (WGS) to correlate the phenotypic resistance and genetic determinants for resistance among M. haemolytica isolates. M. haemolytica (n=276), P. multocida (n=253), and H. somni (n=78) were isolated from feedlot cattle diagnosed with BRD. Gamithromycin susceptibility was determined by broth microdilution. Whole-genome sequencing was utilized to determine the presence/absence of macrolide resistance genes and to genetically type M. haemolytica. Generalized linear mixed models were built for analysis. There was not a significant difference between MM and CON groups in regards to the likelihood of culturing a resistant isolate of M. haemolytica or P. multocida. The likelihood of culturing a resistant isolate of M. haemolytica differed significantly by state of origin in this study. A single M. haemolytica genetic subtype was associated with an over whelming majority of the observed resistance. H. somni isolation counts were low and statistical models would not converge. Phenotypic resistance was predicted with high sensitivity and specificity by WGS. Additional studies to elucidate the relationships between phenotypic expression of resistance/genetic determinants for resistance and clinical response to antimicrobials are necessary to inform judicious use of antimicrobials in the context of relieving animal disease and suffering.

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Section: Discussionmentioning

confidence: 87%

Observations on macrolide resistance and susceptibility testing performance in field isolates collected from clinical bovine respiratory disease cases

DeDonder

Harhay

Apley

et al. 2016

Veterinary Microbiology

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“…Treatments that offer dual antimicrobial and anti-inflammatory/pro-resolution actions may yield superior clinical benefits during bacterial infections ( 13 , 32 – 34 ). The present study, using a model of tylvalosin-induced immunomodulation in porcine neutrophils and macrophages, reveals a novel antibiotic-induced release of the potent pro-resolution mediators RvD 1 and LXA 4 by neutrophils.…”

Section: Discussionmentioning

confidence: 99%

“…RvD 1 , as well as its aspirin-triggered epimer, play a central role in the self-resolution of gram-negative bacterial pneumonia ( 30 , 31 ). Over the past decade, researchers both in human and veterinary medicine have been screening for therapeutics that may halt self-perpuating inflammation by stimulating anti-inflammatory and/or pro-resolution mediators ( 13 , 32 – 34 ).…”

Section: Introductionmentioning

confidence: 99%

Anti-Inflammatory Benefits of Antibiotics: Tylvalosin Induces Apoptosis of Porcine Neutrophils and Macrophages, Promotes Efferocytosis, and Inhibits Pro-Inflammatory CXCL-8, IL1α, and LTB4 Production, While Inducing the Release of Pro-Resolving Lipoxin A4 and Resolvin D1

et al. 2018

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Excessive accumulation of neutrophils and their uncontrolled death by necrosis at the site of inflammation exacerbates inflammatory responses and leads to self-amplifying tissue injury and loss of organ function, as exemplified in a variety of respiratory diseases. In homeostasis, neutrophils are inactivated by apoptosis, and non phlogistically removed by neighboring macrophages in a process known as efferocytosis, which promotes the resolution of inflammation. The present study assessed the potential anti-inflammatory and pro-resolution benefits of tylvalosin, a recently developed broad-spectrum veterinary macrolide derived from tylosin. Recent findings indicate that tylvalosin may modulate inflammation by suppressing NF-κB activation. Neutrophils and monocyte-derived macrophages were isolated from fresh blood samples obtained from 12- to 22-week-old pigs. Leukocytes exposed to vehicle or to tylvalosin (0.1, 1.0, or 10 µg/mL; 0.096–9.6 µM) were assessed at various time points for apoptosis, necrosis, efferocytosis, and changes in the production of cytokines and lipid mediators. The findings indicate that tylvalosin increases porcine neutrophil and macrophage apoptosis in a concentration- and time-dependent manner, without altering levels of necrosis or reactive oxygen species production. Importantly, tylvalosin increased the release of pro-resolving Lipoxin A4 (LXA4) and Resolvin D1 (RvD1) while inhibiting the production of pro-inflammatory Leukotriene B4 (LTB4) in Ca2+ ionophore-stimulated porcine neutrophils. Tylvalosin increased neutrophil phospholipase C activity, an enzyme involved in releasing arachidonic acid from membrane stores. Tylvalosin also inhibited pro-inflammatory chemokine (C–X–C motif) ligand 8 (CXCL-8, also known as Interleukin-8) and interleukin-1 alpha (IL-1α) protein secretion in bacterial lipopolysaccharide-stimulated macrophages. Together, these data illustrate that tylvalosin has potent immunomodulatory effects in porcine leukocytes in addition to its antimicrobial properties.

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“…Macrolides exert a wide variety of anti‐inflammatory or immunomodulatory effects that might enhance their clinical efficacy including decreased mucus production by epithelial cells and reduced secretion of pro‐inflammatory cytokines by mononuclear and epithelial cells 30. Recent studies indicate that TUL induces apoptosis in bovine neutrophils and macrophages, and inhibits production of pro‐inflammatory mediators by these cells 31, 32, 33. Additional studies will be required to determine the exact mechanism responsible for the efficacy of TUL in the treatment of bronchopneumonia in foals.…”

Section: Discussionmentioning

confidence: 99%

“…30 Recent studies indicate that TUL induces apoptosis in bovine neutrophils and macrophages, and inhibits production of proinflammatory mediators by these cells. [31][32][33] Additional studies will be required to determine the exact mechanism responsible for the efficacy of TUL in the treatment of bronchopneumonia in foals.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Tulathromycin for the Treatment of Foals with Mild to Moderate Bronchopneumonia

Rutenberg¹,

Venner

Giguère

2017

Veterinary Internal Medicne

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BackgroundThere is conflicting data regarding the efficacy of tulathromycin for the treatment of foals with bronchopneumonia.HypothesesTulathromycin is effective for the treatment of bronchopneumonia in foals and noninferior to the combination of azithromycin and rifampin.AnimalsA total of 240 foals on a farm endemic for infections caused by Rhodococcus equi.MethodsIn a controlled, randomized, and double‐blinded clinical trial, foals with ultrasonographic pulmonary lesions (abscess score 10–15 cm) were allocated to 3 groups: 1—tulathromycin IM q 7 days (n = 80); 2—azithromycin‐rifampin, orally q24h (n = 80); or 3—untreated controls (n = 80). Physical examination and thoracic ultrasonography were performed by individuals unaware of treatment group assignment. Foals that worsened were considered treatment failures and removed from the study.ResultsThe proportion of foals that recovered was significantly higher for foals treated with tulathromycin (70 of 79) or azithromycin‐rifampin (76 of 80) compared to that of control foals (22 of 80). The difference in the percentage of efficacy of azithromycin‐rifampin versus tulathromycin was 6.4% (90% CI = −0.72–13.5%). Given that the confidence interval crossed the predetermined noninferiority limit of 10%, the null hypothesis that the response rate in the azithromycin‐rifampin group is superior to that of the tulathromycin group could not be rejected. Resolution of ultrasonographic lesions occurred faster in foals treated with azithromycin‐rifampin than in foals treated with tulathromycin.Conclusion and clinical importanceTulathromycin was effective for the treatment of bronchopneumonia in foals at this farm but not as effective as the combination of azithromycin‐rifampin.

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Tulathromycin Exerts Proresolving Effects in Bovine Neutrophils by Inhibiting Phospholipases and Altering Leukotriene B₄, Prostaglandin E₂, and Lipoxin A₄Production

Cited by 17 publications

References 57 publications

Observations on macrolide resistance and susceptibility testing performance in field isolates collected from clinical bovine respiratory disease cases

Observations on macrolide resistance and susceptibility testing performance in field isolates collected from clinical bovine respiratory disease cases

Anti-Inflammatory Benefits of Antibiotics: Tylvalosin Induces Apoptosis of Porcine Neutrophils and Macrophages, Promotes Efferocytosis, and Inhibits Pro-Inflammatory CXCL-8, IL1α, and LTB4 Production, While Inducing the Release of Pro-Resolving Lipoxin A4 and Resolvin D1

Efficacy of Tulathromycin for the Treatment of Foals with Mild to Moderate Bronchopneumonia

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