Abstract
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 log10 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.
| Original language | English |
|---|---|
| Article number | e00028-18 |
| Number of pages | 13 |
| Journal | Antimicrobial Agents and Chemotherapy |
| Volume | 62 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 1 Jun 2018 |
Keywords
- Antibiotic combination
- Enrofloxacin
- Extensively drug resistant
- Polymyxins
- Pseudomonas aeruginosa
Cite this
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Polymyxin b in combination with enrofloxacin exerts synergistic killing against extensively drug-resistant pseudomonas aeruginosa. / Lin, Yu-Wei; Yu, Heidi H.; Zhao, Jinxin; Han, Mei-Ling; Zhu, Yan; Akter, Jesmin; Wickremasinghe, Hasini; Walpola, Hasini; Wirth, Veronika; Rao, Gauri G.; Forrest, Alan; Velkov, Tony; Li, Jian.
In: Antimicrobial Agents and Chemotherapy, Vol. 62, No. 6, e00028-18, 01.06.2018.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Polymyxin b in combination with enrofloxacin exerts synergistic killing against extensively drug-resistant pseudomonas aeruginosa
AU - Lin, Yu-Wei
AU - Yu, Heidi H.
AU - Zhao, Jinxin
AU - Han, Mei-Ling
AU - Zhu, Yan
AU - Akter, Jesmin
AU - Wickremasinghe, Hasini
AU - Walpola, Hasini
AU - Wirth, Veronika
AU - Rao, Gauri G.
AU - Forrest, Alan
AU - Velkov, Tony
AU - Li, Jian
PY - 2018/6/1
Y1 - 2018/6/1
N2 - 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 log10 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.
AB - 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 log10 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.
KW - Antibiotic combination
KW - Enrofloxacin
KW - Extensively drug resistant
KW - Polymyxins
KW - Pseudomonas aeruginosa
UR - http://www.scopus.com/inward/record.url?scp=85047649622&partnerID=8YFLogxK
U2 - 10.1128/AAC.00028-18
DO - 10.1128/AAC.00028-18
M3 - Article
AN - SCOPUS:85047649622
VL - 62
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 1098-6596
IS - 6
M1 - e00028-18
ER -