Dose dependency of outcomes of intrapleural fibrinolytic therapy in new rabbit empyema models

Abstract

The incidence of empyema (EMP) is increasing worldwide; EMP generally occurs with pleural loculation and impaired drainage is often treated with intrapleural fibrinolytic therapy (IPFT) or surgery. A number of IPFT options are used clinically with empiric dosing and variable outcomes in adults. To evaluate mechanisms governing intrapleural fibrinolysis and disease outcomes, models of Pasteurella multocida and Streptococcus pneumoniae were generated in rabbits and the animals were treated with either human tissue (tPA) plasminogen activator or prourokinase (scuPA). Rabbit EMP was characterized by the development of pleural adhesions detectable by chest ultrasonography and fibrinous coating of the pleura. Similar to human EMP, rabbits with EMP accumulated sizable, 20- to 40-ml fibrinopurulent pleural effusions associated with extensive intrapleural organization, significantly increased pleural thickness, suppression of fibrinolytic and plasminogen-activating activities, and accumulation of high levels of plasminogen activator inhibitor 1, plasminogen, and extracellular DNA. IPFT with tPA (0.145 mg/kg) or scuPA (0.5 mg/kg) was ineffective in rabbit EMP (n = 9 and 3 for P. multocida and S. pneumoniae, respectively); 2 mg/kg tPA or scuPA IPFT (n = 5) effectively cleared S. pneumoniae-induced EMP collections in 24 h with no bleeding observed. Although intrapleural fibrinolytic activity for up to 40 min after IPFT was similar for effective and ineffective doses of fibrinolysin, it was lower for tPA than for scuPA treatments. These results demonstrate similarities between rabbit and human EMP, the importance of pleural fluid PAI-1 activity, and levels of plasminogen in the regulation of intrapleural fibrinolysis and illustrate the dose dependency of IPFT outcomes in EMP.

Precision-guided, Personalized Intrapleural Fibrinolytic Therapy for Empyema and Complicated Parapneumonic Pleural Effusions: The Case for The Fibrinolytic Potential

“…Interestingly, we recently reported that levels of PAI-1 in pleural fluids of patients with empyema and other forms of pleural infection in the MIST2 clinical trial were similar to those detected in the pleural fluids of rabbits with either P. multocida or S. pneumoniae -induced empyema 22 . The levels of PAI-1 antigen and activity varied in individual patients, suggesting that dosing of fibrinolysins could be variably effective in patients depending on the levels of PAI-1 that were present within pleural fluids at the time that IPFT is initiated.…”

“…Testing of the FPA in human pleural fluids suggests that the assay can detect a wide range of variable responses to the same dose of a fibrinolysin added to pleural fluids 22 , suggesting that it is worthy of further investigation. This data clearly demonstrate that a wide range of FPA responses are associated with patients with pleural infection, most of whom had empyema, as reported in the MIST2 trial 4 .…”

“…We recently examined this issue in newly developed rabbit models of progressively organizing pleural empyema that develop as facsimiles of pleural loculation of the course of five days 22 . In this study, we compared the biochemical correlates and phenotypic changes associated with empyema induced by intrapleural administration of either P. multocida or S. pneumoniae .…”

“…These complexes resist inhibition by PAI-1 and lead to durable but low grade maintenance of plasminogen activator release that occurs over about 24h. This particular mode of processing offers potential advantages for scuPA IPFT, which has thus far been well-tolerated in preclinical testing 22, 24, 25, 45–47 and GLP toxicology testing. scuPA is now undergoing safety testing in a Phase I dose escalation clinical trial being conducted in Australia and New Zealand under the sponsorship of Lung Therapeutics, Inc.…”

Resisting the resistance. Is there progress in maintaining antimicrobial efficacy?

“…A rabbit empyema model showed that using concentrations that stayed in the MSW for 40% of the time a 100% selection of mutant strains occurred. 26 Joseph Blondeau's group has established a rat Pseudomonas model showing data on selection of resistance that are not yet published.…”