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A novel in vitro metric predicts in vivo efficacy of inhaled silver-based antimicrobials in a murine Pseudomonas aeruginosa pneumonia model.

ABSTRACT: To address the escalating problem of antimicrobial resistance and the dwindling antimicrobial pipeline, we have developed a library of novel aerosolizable silver-based antimicrobials, particularly for the treatment of pulmonary infections. To rapidly screen this library and identify promising candidates, we have devised a novel in vitro metric, named the "drug efficacy metric" (DEM), which integrates both the antibacterial activity and the on-target, host cell cytotoxicity. DEMs calculated using an on-target human bronchial epithelial cell-line correlates well (R2?>?0.99) with in vivo efficacy, as measured by median survival hours in a Pseudomonas aeruginosa pneumonia mouse model following aerosolized antimicrobial treatment. In contrast, DEMs derived using off-target primary human dermal fibroblasts correlate poorly (R2?=?0.0595), which confirms our hypothesis. SCC1 and SCC22 have been identified as promising drug candidates through these studies, and SCC22 demonstrates a dose-dependent survival advantage compared to sham treatment. Finally, silver-bearing biodegradable nanoparticles were predicted to exhibit excellent in vivo efficacy based on its in vitro DEM value, which was confirmed in our mouse pneumonia model. Thus, the DEM successfully predicted the efficacy of various silver-based antimicrobials, and may serve as an excellent tool for the rapid screening of potential antimicrobial candidates without the need for extensive animal experimentation.

SUBMITTER: Shah PN

PROVIDER: S-EPMC5913254 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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A novel in vitro metric predicts in vivo efficacy of inhaled silver-based antimicrobials in a murine Pseudomonas aeruginosa pneumonia model.

Shah Parth N PN Shah Kush N KN Smolen Justin A JA Tagaev Jasur A JA Torrealba Jose J Zhou Lan L Zhang Shiyi S Zhang Fuwu F Wagers Patrick O PO Panzner Matthew J MJ Youngs Wiley J WJ Wooley Karen L KL Cannon Carolyn L CL

Scientific reports 20180423 1

To address the escalating problem of antimicrobial resistance and the dwindling antimicrobial pipeline, we have developed a library of novel aerosolizable silver-based antimicrobials, particularly for the treatment of pulmonary infections. To rapidly screen this library and identify promising candidates, we have devised a novel in vitro metric, named the "drug efficacy metric" (DEM), which integrates both the antibacterial activity and the on-target, host cell cytotoxicity. DEMs calculated using ...[more]

PMID: 29686296

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Project description:BackgroundPseudomonas aeruginosa pneumonia is commonly treated with systemic antibiotics to ensure adequate treatment of multidrug resistant (MDR) bacteria. However, intravenous (IV) antibiotics often achieve suboptimal pulmonary concentrations. We therefore aimed to evaluate the effect of inhaled amikacin (AMK) plus IV meropenem (MEM) on bactericidal efficacy in a swine model of monolateral MDR P. aeruginosa pneumonia.MethodsWe ventilated 18 pigs with monolateral MDR P. aeruginosa pneumonia for up to 102 h. At 24 h after the bacterial challenge, the animals were randomized to receive 72 h of treatment with either inhaled saline (control), IV MEM only, or IV-MEM plus inhaled AMK (MEM + AMK). We dosed IV MEM at 25 mg/kg every 8 h and inhaled AMK at 400 mg every 12 h. The primary outcomes were the P. aeruginosa burden and histopathological injury in lung tissue. Secondary outcomes included the P. aeruginosa burden in tracheal secretions and bronchoalveolar lavage fluid, the development of antibiotic resistance, the antibiotic distribution, and the levels of inflammatory markers.ResultsThe median (25-75th percentile) P. aeruginosa lung burden for animals in the control, MEM only, and MEM + AMK groups was 2.91 (1.75-5.69), 0.72 (0.12-3.35), and 0.90 (0-4.55) log10 CFU/g (p = 0.009). Inhaled therapy had no effect on preventing dissemination compared to systemic monotherapy, but it did have significantly higher bactericidal efficacy in tracheal secretions only. Remarkably, the minimum inhibitory concentration of MEM increased to > 32 mg/L after 72-h exposure to monotherapy in 83% of animals, while the addition of AMK prevented this increase (p = 0.037). Adjunctive therapy also slightly affected interleukin-1β downregulation. Despite finding high AMK concentrations in pulmonary samples, we found no paired differences in the epithelial lining fluid concentration between infected and non-infected lungs. Finally, a non-significant trend was observed for higher amikacin penetration in low-affected lung areas.ConclusionsIn a swine model of monolateral MDR P. aeruginosa pneumonia, resistant to the inhaled AMK and susceptible to the IV antibiotic, the use of AMK as an adjuvant treatment offered no benefits for either the colonization of pulmonary tissue or the prevention of pathogen dissemination. However, inhaled AMK improved bacterial eradication in the proximal airways and hindered antibiotic resistance.

Project description:UnlabelledCystic fibrosis (CF) is a heritable disease characterized by chronic, polymicrobial lung infections. While Staphylococcus aureus is the dominant lung pathogen in young CF patients, Pseudomonas aeruginosa becomes predominant by adulthood. P. aeruginosa produces a variety of antimicrobials that likely contribute to this shift in microbial populations. In particular, secretion of 2-alkyl-4(1H)-quinolones (AQs) contributes to lysis of S. aureus in coculture, providing an iron source to P. aeruginosa both in vitro and in vivo. We previously showed that production of one such AQ, the Pseudomonas quinolone signal (PQS), is enhanced by iron depletion and that this induction is dependent upon the iron-responsive PrrF small RNAs (sRNAs). Here, we demonstrate that antimicrobial activity against S. aureus during coculture is also enhanced by iron depletion, and we provide evidence that multiple AQs contribute to this activity. Strikingly, a P. aeruginosa ΔprrF mutant, which produces very little PQS in monoculture, was capable of mediating iron-regulated growth suppression of S. aureus. We show that the presence of S. aureus suppresses the ΔprrF1,2 mutant's defect in iron-regulated PQS production, indicating that a PrrF-independent iron regulatory pathway mediates AQ production in coculture. We further demonstrate that iron-regulated antimicrobial production is conserved in multiple P. aeruginosa strains, including clinical isolates from CF patients. These results demonstrate that iron plays a central role in modulating interactions of P. aeruginosa with S. aureus. Moreover, our studies suggest that established iron regulatory pathways of these pathogens are significantly altered during polymicrobial infections.ImportanceChronic polymicrobial infections involving Pseudomonas aeruginosa and Staphylococcus aureus are a significant cause of morbidity and mortality, as the interplay between these two organisms exacerbates infection. This is in part due to enhanced production of antimicrobial metabolites by P. aeruginosa when these two species are cocultured. Using both established and newly developed coculture techniques, this report demonstrates that iron depletion increases P. aeruginosa's ability to suppress growth of S. aureus. These findings present a novel role for iron in modulating microbial interaction and provide the basis for understanding how essential nutrients drive polymicrobial infections.

Project description:BackgroundCefepime/taniborbactam is a cephalosporin/bicyclic boronate β-lactamase inhibitor combination in clinical development for nosocomial pneumonia due to MDR Gram-negative bacteria. A murine pneumonia model was used to characterize cefepime/taniborbactam in vivo pharmacodynamics against Enterobacterales and Pseudomonas aeruginosa strains.MethodsClinical cefepime-non-susceptible Enterobacterales and P. aeruginosa strains expressing serine carbapenemases and/or other cefepime-hydrolysing β-lactamases with cefepime/taniborbactam combination MICs of 0.12-16 mg/L were used. Cefepime and taniborbactam human-simulated regimens equivalent to clinical doses (i.e. 2/0.5 g q8h) were established in the pneumonia model. The in vivo activity of the cefepime human-simulated regimen given alone or concomitantly with escalating taniborbactam exposures against eight Enterobacterales and four P. aeruginosa strains was assessed. Taniborbactam pharmacokinetics were evaluated to determine systemic exposures of regimens used; taniborbactam fAUC0-24/MIC values required for efficacy were estimated using the Hill equation. In addition, the in vivo activity of the cefepime/taniborbactam combination human-simulated regimen was assessed against 18 strains.ResultsAmong Enterobacterales, median taniborbactam fAUC0-24/MIC values associated with stasis and 1 log kill were 0.96 and 4.03, respectively, while for P. aeruginosa, requirements were 1.35 and 3.02 for stasis and 1 log kill, respectively. The cefepime/taniborbactam human-simulated regimen produced >2 log kill in 14/18 strains and >1 log kill in 18/18 strains.ConclusionsCefepime/taniborbactam produced marked in vivo bactericidal activity against cefepime-non-susceptible Enterobacterales and P. aeruginosa isolates with cefepime/taniborbactam MICs up to and including 16 mg/L in the pneumonia model. Assessments of the probability of clinical attainment of the identified targets should be undertaken to support the selected cefepime/taniborbactam dose for treatment of nosocomial pneumonia.

Dataset Information

A novel in vitro metric predicts in vivo efficacy of inhaled silver-based antimicrobials in a murine Pseudomonas aeruginosa pneumonia model.

Publications

A novel in vitro metric predicts in vivo efficacy of inhaled silver-based antimicrobials in a murine Pseudomonas aeruginosa pneumonia model.

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