Development and validation of a rabbit model of Pseudomonas aeruginosa non-ventilated pneumonia for preclinical drug development.

Background: New drugs targeting antimicrobial resistant pathogens, including Pseudomonas aeruginosa, have been challenging to evaluate in clinical trials, particularly for the non-ventilated hospital-acquired pneumonia and ventilator-associated pneumonia indications. Development of new antibacterial drugs is facilitated by preclinical animal models that could predict clinical efficacy in patients with these infections. Methods: We report here an FDA-funded study to develop a rabbit model of non-ventilated pneumonia with Pseudomonas aeruginosa by determining the extent to which the natural history of animal disease reproduced human pathophysiology and conducting validation studies to evaluate whether humanized dosing regimens of two antibiotics, meropenem and tobramycin, can halt or reverse disease progression. Results: In a rabbit model of non-ventilated pneumonia, endobronchial challenge with live P. aeruginosa strain 6206, but not with UV-killed Pa6206, caused acute respiratory distress syndrome, as evidenced by acute lung inflammation, pulmonary edema, hemorrhage, severe hypoxemia, hyperlactatemia, neutropenia, thrombocytopenia, and hypoglycemia, which preceded respiratory failure and death. Pa6206 increased >100-fold in the lungs and then disseminated from there to infect distal organs, including spleen and kidneys. At 5 h post-infection, 67% of Pa6206-challenged rabbits had PaO2 <60 mmHg, corresponding to a clinical cut-off when oxygen therapy would be required. When administered at 5 h post-infection, humanized dosing regimens of tobramycin and meropenem reduced mortality to 17-33%, compared to 100% for saline-treated rabbits (P<0.001 by log-rank tests). For meropenem which exhibits time-dependent bactericidal activity, rabbits treated with a humanized meropenem dosing regimen of 80 mg/kg q2h for 24 h achieved 100% T>MIC, resulting in 75% microbiological clearance rate of Pa6206 from the lungs. For tobramycin which exhibits concentration-dependent killing, rabbits treated with a humanized tobramycin dosing regimen of 8 mg/kg q8h for 24 h achieved Cmax/MIC of 9.8 ± 1.4 at 60 min post-dose, resulting in 50% lung microbiological clearance rate. In contrast, rabbits treated with a single tobramycin dose of 2.5 mg/kg had Cmax/MIC of 7.8 ± 0.8 and 8% (1/12) microbiological clearance rate, indicating that this rabbit model can detect dose-response effects. Conclusion: The rabbit model may be used to help predict clinical efficacy of new antibacterial drugs for the treatment of non-ventilated P. aeruginosa pneumonia.

A Retrospective Global Assessment of Factors Associated With COVID-19 Policies and Health Outcomes.

Background: The 2019 Global Health Security (GHS) Index measured the capacities of countries to prepare for and respond to epidemics and pandemics. However, the COVID-19 pandemic revealed that GHS Index scores were poorly correlated with ability to respond to infectious disease threats. It is critical to understand how public health policies may reduce the negative impacts of pandemics. Objective: To identify non-pharmaceutical interventions (NPIs) that can minimize morbidity and mortality during the COVID-19 and future pandemics, this study examined associations between country characteristics, NPI public health policies, and COVID-19 outcomes during the first year of the pandemic, prior to the introduction of the COVID-19 vaccine. This global analysis describes worldwide trends in policy implementation and generates a stronger understanding of how NPIs contributed to improved health outcomes. Design: This cross-sectional, retrospective study relied on information drawn from publicly available datasets through December 31, 2020. Primary and Secondary Outcome Measures: We conducted multivariate regressions to examine associations between country characteristics and policies, and policies and health outcomes. Results: Countries with higher health service coverage prior to the pandemic implemented more policies and types of policies. Countries with more bordering countries implemented more border control policies (0.78**), and countries with denser populations implemented more masking policies (0.24*). Across all countries, fewer COVID-19 cases and deaths per million were associated with masking (-496.10*, -7.57), testing and tracing (-108.50**, -2.47**), and restriction of movement (-102.30*, -2.10*) policies, with stronger associations when these policies were mandatory rather than voluntary. Conclusions: Country characteristics, including health service coverage, number of bordering countries, and population density, may predict the frequency and nature of public health interventions. Countries with higher health service coverage may have the infrastructure to react more efficiently to a pandemic, leading them to implement a greater number of policies. Mandatory masking, testing and tracing, and restriction of movement policies were associated with more favorable COVID-19 population health outcomes. While these results are consistent with existing COVID-19 mathematical models, policy effectiveness depends on how well they are implemented. Our results suggest that social distancing policies were less effective in reducing infectious disease risk, which may reflect difficulties with enforcement and monitoring.

Pseudomonas aeruginosa Ventilator-Associated Pneumonia Rabbit Model for Preclinical Drug Development.

Development and validation of large animal models of Pseudomonas aeruginosa ventilator-associated pneumonia are needed for testing new drug candidates in a manner that mimics how they will be used clinically. We developed a new model in which rabbits were ventilated with low tidal volume and challenged with P. aeruginosa to recapitulate hallmark clinical features of acute respiratory distress syndrome (ARDS): acute lung injury and inflammation, progressive decrease in arterial oxygen partial pressure to fractional inspired oxygen PaO2:FiO2, leukopenia, neutropenia, thrombocytopenia, hyperlactatemia, severe hypotension, bacterial dissemination from lung to other organs, multiorgan dysfunction, and ultimately death. We evaluated the predictive power of this rabbit model for antibiotic efficacy testing by determining whether a humanized dosing regimen of meropenem, a potent antipseudomonal ß-lactam antibiotic, when administered with or without intensive care unit (ICU)-supportive care (fluid challenge and norepinephrine), could halt or reverse natural disease progression. Our humanized meropenem dosing regimen produced a plasma concentration-time profile in the rabbit model similar to those reported in patients with ventilator-associated bacterial pneumonia. In this rabbit model, treatment with humanized meropenem and ICU-supportive care achieved the highest level of survival, halted the worsening of ARDS biomarkers, and reversed lethal hypotension, although treatment with humanized meropenem alone also conferred some protection compared to treatment with placebo (saline) alone or placebo plus ICU-supportive care. In conclusion, this rabbit model could help predict whether an antibiotic will be efficacious for the treatment of human ventilator-associated pneumonia.