Efficacy of Aerosolized Rifaximin versus Tobramycin for Treatment of Pseudomonas aeruginosa Pneumonia in Mice

Abstract

Pseudomonas aeruginosa is a Gram-negative opportunistic bacterial pathogen that can cause chronic lung infections in patients with cystic fibrosis (CF). The current preferred treatment for CF lung infections includes inhaled tobramycin (TOB); however, studies suggest TOB cannot effectively inhibit biofilm formation. Using an NIH small compounds drug library approved for safe use in humans, we identified rifaximin (RFX), a semisynthetic, rifamycin family, nonsystemic antibiotic that inhibits alginate production and growth in P. aeruginosa. Inhibition of alginate production was further analyzed using the uronic acid carbazole assay and a promoter reporter assay that measures the transcription of the alginate biosynthetic operon. Compared to TOB, RFX significantly reduced alginate production in laboratory and CF sputum isolates of P. aeruginosa. In addition, RFX showed a narrow range of MICs when measured with multidrug-resistant bacterial species of clinical relevance, synergistic activities with TOB or amikacin against clinical isolates, as well as reduction toward in vitro preformed biofilms. In C57BL/6 mice, penetration of nebulized TOB into the lungs was shown at a higher level than that of RFX. Further, in vivo assessment using a DBA/2 mouse lung infection model found increased survival rates with a single-dose treatment of nebulized RFX and decreased P. aeruginosa PAO1 bioburden with a multiple-dose treatment of RFX plus TOB. In addition, mice treated with a single exposure to dimethyl sulfoxide (DMSO), a solvent that dissolves RFX, showed no apparent toxicity. In summary, RFX may be used to supplement TOB inhalation therapy to increase efficacy against P. aeruginosa biofilm infections.

Variability of murine bacterial pneumonia models used to evaluate antimicrobial agents

“…Following the exclusion of additional studies that focused on interventions or therapies other than small molecule antibiotics (monoclonal antibodies, bacteriophages, metal chelators, plant extracts, Lactobacillus , etc. ), 53 studies remained ( López-Rojas et al, 2011 ; Pachón-Ibáñez et al, 2011 ; Docobo-Pérez et al, 2012 ; Tang et al, 2012 ; Wang et al, 2012 ; Yamada et al, 2012 , 2013a , b ; He et al, 2013 ; Hirsch et al, 2013 ; Jacqueline et al, 2013 ; Louie et al, 2013 , 2015 ; Harada et al, 2014 ; Hengzhuang et al, 2014 ; Yokoyama et al, 2014 ; Bowers et al, 2015 ; Cheah et al, 2015 ; Berkhout et al, 2016 ; Brunetti et al, 2016 ; Cigana et al, 2016 ; Lepak and Andes, 2016 ; Mardirossian et al, 2016 ; McCaughey et al, 2016 ; Parra Millán et al, 2016 ; Thabit et al, 2016 ; Yang et al, 2016 ; Kaku et al, 2017a , b ; Li Y. T. et al, 2017 , Li Y. et al, 2017 ; Lin et al, 2017a , b , 2018 ; Oshima et al, 2017 ; Sakoulas et al, 2017 ; Zhou J. et al, 2017 , Zhou Y. F. et al, 2017 ; Avery et al, 2018 ; Chen et al, 2018 ; de Paula et al, 2018 ; Geller et al, 2018 ; Lou et al, 2018 ; Monogue et al, 2018 ; Kirby et al, 2019 ; Ku et al, 2019 ; Nakamura et al, 2019 ; Ren et al, 2019 ; Sanderink et al, 2019 ; Zhao et al, 2019 ; Johnson et al, 2020 ; Tan et al, 2020 ; Ma X. L. et al, 2020 ; Supplementary Table 2 ). Murine model variables were extracted from these articles to generate a data set for further analyses of experimental conditions.…”

“…We observed that the vast majority of the studies were carried out in female mice regardless of the bacteria used for infection ( Table 2 ). Interestingly, only one study used both female and male mice in separate experiments with different readouts ( Kirby et al, 2019 ; Table 2 ). Female C57BL/6J mice have been shown to be more susceptible to A. baumannii lung infection than their male counterparts ( Pires et al, 2020 ).…”

Treatment of severe pneumonia by hinokitiol in a murine antimicrobial-resistant pneumococcal pneumonia model

“…Clinically, treatment of infectious diseases requires thorough bactericidal effect until the infectious inflammation is resolved [39,40]. Therefore, a repeated dose of antibiotics is often prescribed to maintain an adequate concentration of the drug at the site of infection [41][42][43]. Our repeated administration experiment showed that although single or two-time hinokitiol administration did not significantly lower the bacterial load 4 days after infection, repeating the procedure three times successfully decreased the bacterial load in the mouse pneumonia model.…”

Random Peptide Mixtures as Safe and Effective Antimicrobials against Pseudomonas aeruginosa and MRSA in Mouse Models of Bacteremia and Pneumonia

“…In the bacteremia model, both FK20 and FdK attenuated the burden of PAO1 in spleens by 1.37 and 1.41 log and USA300 LAC burden in spleens by 1.90 and 1.86 log, respectively (Figure 5B,C). In mouse studies with conventional antibiotics, pneumonia models showed a 2.5-(P. aeruginosa, tobramycin) 45 and 1.5-log (MRSA, vancomycin) 46 decrease in CFUs, while sepsis models had a 3-log (P. aeruginosa, colistin, and MRSA, vancomycin) 46,47 decrease in CFUs. One important note is that the therapeutic dose of FK20 and FdK (10 mg/kg) was ∼5× higher than that of the FK20− Cy7.5 used for the live IVIS-based imaging.…”