In vitro and in vivo efficacy of minocycline-based therapy for Elizabethkingia anophelis and the impact of reduced minocycline susceptibility

•Minocycline improved the survival of Galleria mellonella and mice infected with susceptible Elizabethkingia anophelis and reduced the tissue bacterial load of mice.•Reduced minocycline susceptibility (MIC of 4 mg/L) due to spontaneous mutation was associated with poor treatment outcomes in Galleria...

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Published in:International journal of antimicrobial agents 2022-11, Vol.60 (5-6), p.106678-106678, Article 106678
Main Authors: Yang, Ya-Sung, Huang, Tzu-Wen, Huang, Ying-Chi, Huang, Wei-Cheng, Hsu, Shu-Yuan, Wu, Han-Chieh, Chen, Feng-Jui, Shang, Hung-Sheng, Sytwu, Huey-Kang, Kuo, Shu-Chen
Format: Article
Language:English
Subjects:
Animals
Anti-Bacterial Agents - pharmacology
Anti-Bacterial Agents - therapeutic use
Combination therapy
Efficacy
Elizabethkingia
Flavobacteriaceae
Mice
Microbial Sensitivity Tests
Minocycline
Minocycline - pharmacology
Minocycline - therapeutic use
Reduced minocycline susceptibility
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Summary:•Minocycline improved the survival of Galleria mellonella and mice infected with susceptible Elizabethkingia anophelis and reduced the tissue bacterial load of mice.•Reduced minocycline susceptibility (MIC of 4 mg/L) due to spontaneous mutation was associated with poor treatment outcomes in Galleria mellonella and mice.•The addition of rifampin (1 mg/L) reduced the mutant prevention concentration of minocycline from 2–4 mg/L to < 0.5 mg/L.•Rifampin combined with minocycline was synergistic in vitro, but conferred no in vivo benefit. Elizabethkingia anophelis is inherently resistant to multiple antibiotics, except minocycline. This study aimed to determine the in vitro and in vivo efficacy of minocycline monotherapy and combination therapy against susceptible strains and the impact of reduced minocycline susceptibility. Three clinical isolates and one laboratory-induced mutant with reduced minocycline susceptibility were included. Time-kill and checkerboard assays were used to assess in vitro efficacy and synergy, respectively. Galleria mellonella infection and mouse pneumonia models were used to assess in vivo efficacy, and a mouse thigh infection model was used to determine the bacterial load. Minocycline monotherapy exerted a modest inhibitory effect on three clinical minocycline-susceptible E. anophelis isolates in vitro, but delayed G. mellonella death and improved infected mouse survival; it also significantly reduced the in vivo bacterial load. Minocycline had decreased efficacy on G. mellonella and mice infected by the mutant with reduced minocycline susceptibility. Genome comparison revealed several spontaneous mutations associated with reduced minocycline susceptibility. Among eight antibiotics tested in combination with minocycline, rifampin consistently showed in vitro synergy. The addition of rifampin (1 mg/L) reduced the mutant prevention concentration of minocycline from 2–4 mg/L to < 0.5 mg/L. However, compared with monotherapy, the combination of rifampin and minocycline did not further reduce the bacterial load or improve the survival of G. mellonella or mice. Minocycline monotherapy was in vivo effective against susceptible E. anophelis. Reduced minocycline susceptibility due to spontaneous mutation decreased its therapeutic efficacy. In combination with rifampin, it prevented the in vitro emergence of reduced susceptibility but did not provide additional in vivo survival benefit.
ISSN:0924-8579
1872-7913
DOI:10.1016/j.ijantimicag.2022.106678