Polymyxin B in Combination with Enrofloxacin Exerts Synergistic Killing against Extensively Drug-Resistant Pseudomonas aeruginosa [Pharmacology]

Publication Date:
2018-05-26
Publisher:
The American Society for Microbiology (ASM)
Print ISSN:
0066-4804
Electronic ISSN:
1098-6596
Topics:
Biology
Medicine
Published by:
http://www.asm.org/
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autor Lin, Y.-W., Yu, H. H., Zhao, J., Han, M.-L., Zhu, Y., Akter, J., Wickremasinghe, H., Walpola, H., Wirth, V., Rao, G. G., Forrest, A., Velkov, T., Li, J.
beschreibung Polymyxins are increasingly used as a last-resort class of antibiotics against extensively drug-resistant (XDR) Gram-negative bacteria. However, resistance to polymyxins can emerge with monotherapy. As nephrotoxicity is the major dose-limiting factor for polymyxin monotherapy, dose escalation to suppress the emergence of polymyxin resistance is not a viable option. Therefore, novel approaches are needed to preserve this last-line class of antibiotics. This study aimed to investigate the antimicrobial synergy of polymyxin B combined with enrofloxacin against Pseudomonas aeruginosa . Static time-kill studies were conducted over 24 h with polymyxin B (1 to 4 mg/liter) and enrofloxacin (1 to 4 mg/liter) alone or in combination. Additionally, in vitro one-compartment model (IVM) and hollow-fiber infection model (HFIM) experiments were performed against P. aeruginosa 12196. Polymyxin B and enrofloxacin in monotherapy were ineffective against all of the P. aeruginosa isolates examined, whereas polymyxin B-enrofloxacin in combination was synergistic against P. aeruginosa , with ≥2 to 4 log 10 kill at 24 h in the static time-kill studies. In both IVM and HFIM, the combination was synergistic, and the bacterial counting values were below the limit of quantification on day 5 in the HFIM. A population analysis profile indicated that the combination inhibited the emergence of polymyxin resistance in P. aeruginosa 12196. The mechanism-based modeling suggests that the synergistic killing is a result of the combination of mechanistic and subpopulation synergy. Overall, this is the first preclinical study to demonstrate that the polymyxin-enrofloxacin combination is of considerable utility for the treatment of XDR P. aeruginosa infections and warrants future clinical evaluations.
citation_standardnr 6267445
datenlieferant ipn_articles
feed_id 515
feed_publisher The American Society for Microbiology (ASM)
feed_publisher_url http://www.asm.org/
insertion_date 2018-05-26
journaleissn 1098-6596
journalissn 0066-4804
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher The American Society for Microbiology (ASM)
quelle Antimicrobial Agents and Chemotherapy
relation http://aac.asm.org/cgi/content/short/62/6/e00028-18?rss=1
search_space articles
shingle_author_1 Lin, Y.-W., Yu, H. H., Zhao, J., Han, M.-L., Zhu, Y., Akter, J., Wickremasinghe, H., Walpola, H., Wirth, V., Rao, G. G., Forrest, A., Velkov, T., Li, J.
shingle_author_2 Lin, Y.-W., Yu, H. H., Zhao, J., Han, M.-L., Zhu, Y., Akter, J., Wickremasinghe, H., Walpola, H., Wirth, V., Rao, G. G., Forrest, A., Velkov, T., Li, J.
shingle_author_3 Lin, Y.-W., Yu, H. H., Zhao, J., Han, M.-L., Zhu, Y., Akter, J., Wickremasinghe, H., Walpola, H., Wirth, V., Rao, G. G., Forrest, A., Velkov, T., Li, J.
shingle_author_4 Lin, Y.-W., Yu, H. H., Zhao, J., Han, M.-L., Zhu, Y., Akter, J., Wickremasinghe, H., Walpola, H., Wirth, V., Rao, G. G., Forrest, A., Velkov, T., Li, J.
shingle_catch_all_1 Polymyxin B in Combination with Enrofloxacin Exerts Synergistic Killing against Extensively Drug-Resistant Pseudomonas aeruginosa [Pharmacology]
Polymyxins are increasingly used as a last-resort class of antibiotics against extensively drug-resistant (XDR) Gram-negative bacteria. However, resistance to polymyxins can emerge with monotherapy. As nephrotoxicity is the major dose-limiting factor for polymyxin monotherapy, dose escalation to suppress the emergence of polymyxin resistance is not a viable option. Therefore, novel approaches are needed to preserve this last-line class of antibiotics. This study aimed to investigate the antimicrobial synergy of polymyxin B combined with enrofloxacin against Pseudomonas aeruginosa . Static time-kill studies were conducted over 24 h with polymyxin B (1 to 4 mg/liter) and enrofloxacin (1 to 4 mg/liter) alone or in combination. Additionally, in vitro one-compartment model (IVM) and hollow-fiber infection model (HFIM) experiments were performed against P. aeruginosa 12196. Polymyxin B and enrofloxacin in monotherapy were ineffective against all of the P. aeruginosa isolates examined, whereas polymyxin B-enrofloxacin in combination was synergistic against P. aeruginosa , with ≥2 to 4 log 10 kill at 24 h in the static time-kill studies. In both IVM and HFIM, the combination was synergistic, and the bacterial counting values were below the limit of quantification on day 5 in the HFIM. A population analysis profile indicated that the combination inhibited the emergence of polymyxin resistance in P. aeruginosa 12196. The mechanism-based modeling suggests that the synergistic killing is a result of the combination of mechanistic and subpopulation synergy. Overall, this is the first preclinical study to demonstrate that the polymyxin-enrofloxacin combination is of considerable utility for the treatment of XDR P. aeruginosa infections and warrants future clinical evaluations.
Lin, Y.-W., Yu, H. H., Zhao, J., Han, M.-L., Zhu, Y., Akter, J., Wickremasinghe, H., Walpola, H., Wirth, V., Rao, G. G., Forrest, A., Velkov, T., Li, J.
The American Society for Microbiology (ASM)
0066-4804
00664804
1098-6596
10986596
shingle_catch_all_2 Polymyxin B in Combination with Enrofloxacin Exerts Synergistic Killing against Extensively Drug-Resistant Pseudomonas aeruginosa [Pharmacology]
Polymyxins are increasingly used as a last-resort class of antibiotics against extensively drug-resistant (XDR) Gram-negative bacteria. However, resistance to polymyxins can emerge with monotherapy. As nephrotoxicity is the major dose-limiting factor for polymyxin monotherapy, dose escalation to suppress the emergence of polymyxin resistance is not a viable option. Therefore, novel approaches are needed to preserve this last-line class of antibiotics. This study aimed to investigate the antimicrobial synergy of polymyxin B combined with enrofloxacin against Pseudomonas aeruginosa . Static time-kill studies were conducted over 24 h with polymyxin B (1 to 4 mg/liter) and enrofloxacin (1 to 4 mg/liter) alone or in combination. Additionally, in vitro one-compartment model (IVM) and hollow-fiber infection model (HFIM) experiments were performed against P. aeruginosa 12196. Polymyxin B and enrofloxacin in monotherapy were ineffective against all of the P. aeruginosa isolates examined, whereas polymyxin B-enrofloxacin in combination was synergistic against P. aeruginosa , with ≥2 to 4 log 10 kill at 24 h in the static time-kill studies. In both IVM and HFIM, the combination was synergistic, and the bacterial counting values were below the limit of quantification on day 5 in the HFIM. A population analysis profile indicated that the combination inhibited the emergence of polymyxin resistance in P. aeruginosa 12196. The mechanism-based modeling suggests that the synergistic killing is a result of the combination of mechanistic and subpopulation synergy. Overall, this is the first preclinical study to demonstrate that the polymyxin-enrofloxacin combination is of considerable utility for the treatment of XDR P. aeruginosa infections and warrants future clinical evaluations.
Lin, Y.-W., Yu, H. H., Zhao, J., Han, M.-L., Zhu, Y., Akter, J., Wickremasinghe, H., Walpola, H., Wirth, V., Rao, G. G., Forrest, A., Velkov, T., Li, J.
The American Society for Microbiology (ASM)
0066-4804
00664804
1098-6596
10986596
shingle_catch_all_3 Polymyxin B in Combination with Enrofloxacin Exerts Synergistic Killing against Extensively Drug-Resistant Pseudomonas aeruginosa [Pharmacology]
Polymyxins are increasingly used as a last-resort class of antibiotics against extensively drug-resistant (XDR) Gram-negative bacteria. However, resistance to polymyxins can emerge with monotherapy. As nephrotoxicity is the major dose-limiting factor for polymyxin monotherapy, dose escalation to suppress the emergence of polymyxin resistance is not a viable option. Therefore, novel approaches are needed to preserve this last-line class of antibiotics. This study aimed to investigate the antimicrobial synergy of polymyxin B combined with enrofloxacin against Pseudomonas aeruginosa . Static time-kill studies were conducted over 24 h with polymyxin B (1 to 4 mg/liter) and enrofloxacin (1 to 4 mg/liter) alone or in combination. Additionally, in vitro one-compartment model (IVM) and hollow-fiber infection model (HFIM) experiments were performed against P. aeruginosa 12196. Polymyxin B and enrofloxacin in monotherapy were ineffective against all of the P. aeruginosa isolates examined, whereas polymyxin B-enrofloxacin in combination was synergistic against P. aeruginosa , with ≥2 to 4 log 10 kill at 24 h in the static time-kill studies. In both IVM and HFIM, the combination was synergistic, and the bacterial counting values were below the limit of quantification on day 5 in the HFIM. A population analysis profile indicated that the combination inhibited the emergence of polymyxin resistance in P. aeruginosa 12196. The mechanism-based modeling suggests that the synergistic killing is a result of the combination of mechanistic and subpopulation synergy. Overall, this is the first preclinical study to demonstrate that the polymyxin-enrofloxacin combination is of considerable utility for the treatment of XDR P. aeruginosa infections and warrants future clinical evaluations.
Lin, Y.-W., Yu, H. H., Zhao, J., Han, M.-L., Zhu, Y., Akter, J., Wickremasinghe, H., Walpola, H., Wirth, V., Rao, G. G., Forrest, A., Velkov, T., Li, J.
The American Society for Microbiology (ASM)
0066-4804
00664804
1098-6596
10986596
shingle_catch_all_4 Polymyxin B in Combination with Enrofloxacin Exerts Synergistic Killing against Extensively Drug-Resistant Pseudomonas aeruginosa [Pharmacology]
Polymyxins are increasingly used as a last-resort class of antibiotics against extensively drug-resistant (XDR) Gram-negative bacteria. However, resistance to polymyxins can emerge with monotherapy. As nephrotoxicity is the major dose-limiting factor for polymyxin monotherapy, dose escalation to suppress the emergence of polymyxin resistance is not a viable option. Therefore, novel approaches are needed to preserve this last-line class of antibiotics. This study aimed to investigate the antimicrobial synergy of polymyxin B combined with enrofloxacin against Pseudomonas aeruginosa . Static time-kill studies were conducted over 24 h with polymyxin B (1 to 4 mg/liter) and enrofloxacin (1 to 4 mg/liter) alone or in combination. Additionally, in vitro one-compartment model (IVM) and hollow-fiber infection model (HFIM) experiments were performed against P. aeruginosa 12196. Polymyxin B and enrofloxacin in monotherapy were ineffective against all of the P. aeruginosa isolates examined, whereas polymyxin B-enrofloxacin in combination was synergistic against P. aeruginosa , with ≥2 to 4 log 10 kill at 24 h in the static time-kill studies. In both IVM and HFIM, the combination was synergistic, and the bacterial counting values were below the limit of quantification on day 5 in the HFIM. A population analysis profile indicated that the combination inhibited the emergence of polymyxin resistance in P. aeruginosa 12196. The mechanism-based modeling suggests that the synergistic killing is a result of the combination of mechanistic and subpopulation synergy. Overall, this is the first preclinical study to demonstrate that the polymyxin-enrofloxacin combination is of considerable utility for the treatment of XDR P. aeruginosa infections and warrants future clinical evaluations.
Lin, Y.-W., Yu, H. H., Zhao, J., Han, M.-L., Zhu, Y., Akter, J., Wickremasinghe, H., Walpola, H., Wirth, V., Rao, G. G., Forrest, A., Velkov, T., Li, J.
The American Society for Microbiology (ASM)
0066-4804
00664804
1098-6596
10986596
shingle_title_1 Polymyxin B in Combination with Enrofloxacin Exerts Synergistic Killing against Extensively Drug-Resistant Pseudomonas aeruginosa [Pharmacology]
shingle_title_2 Polymyxin B in Combination with Enrofloxacin Exerts Synergistic Killing against Extensively Drug-Resistant Pseudomonas aeruginosa [Pharmacology]
shingle_title_3 Polymyxin B in Combination with Enrofloxacin Exerts Synergistic Killing against Extensively Drug-Resistant Pseudomonas aeruginosa [Pharmacology]
shingle_title_4 Polymyxin B in Combination with Enrofloxacin Exerts Synergistic Killing against Extensively Drug-Resistant Pseudomonas aeruginosa [Pharmacology]
timestamp 2025-06-30T23:35:07.282Z
titel Polymyxin B in Combination with Enrofloxacin Exerts Synergistic Killing against Extensively Drug-Resistant Pseudomonas aeruginosa [Pharmacology]
titel_suche Polymyxin B in Combination with Enrofloxacin Exerts Synergistic Killing against Extensively Drug-Resistant Pseudomonas aeruginosa [Pharmacology]
topic W
WW-YZ
uid ipn_articles_6267445