Synergistic killing of NDM-producing MDR Klebsiella pneumoniae by two ‘old’ antibiotics—polymyxin B and chloramphenicol

Rahim, Nusaibah Abdul, Cheah, Soon-Ee, Johnson, Matthew D., Yu, Heidi, Sidjabat, Hanna E., Boyce, John, Butler, Mark S., Cooper, Matthew A., Fu, Jing, Paterson, David L., Nation, Roger L., Bergen, Phillip J., Velkov, Tony and Li, Jian (2015) Synergistic killing of NDM-producing MDR Klebsiella pneumoniae by two ‘old’ antibiotics—polymyxin B and chloramphenicol. Journal of Antimicrobial Chemotherapy, 70 9: 2589-2597. doi:10.1093/jac/dkv135


Author Rahim, Nusaibah Abdul
Cheah, Soon-Ee
Johnson, Matthew D.
Yu, Heidi
Sidjabat, Hanna E.
Boyce, John
Butler, Mark S.
Cooper, Matthew A.
Fu, Jing
Paterson, David L.
Nation, Roger L.
Bergen, Phillip J.
Velkov, Tony
Li, Jian
Title Synergistic killing of NDM-producing MDR Klebsiella pneumoniae by two ‘old’ antibiotics—polymyxin B and chloramphenicol
Formatted title
Synergistic killing of NDM-producing MDR Klebsiella pneumoniae by two ‘old’ antibiotics—polymyxin B and chloramphenicol
Journal name Journal of Antimicrobial Chemotherapy   Check publisher's open access policy
ISSN 0305-7453
1460-2091
Publication date 2015-01-01
Year available 2015
Sub-type Article (original research)
DOI 10.1093/jac/dkv135
Open Access Status Not Open Access
Volume 70
Issue 9
Start page 2589
End page 2597
Total pages 9
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
Formatted abstract
Objectives Combination therapy is an important option in the fight against Gram-negative ‘superbugs’. This study systematically investigated bacterial killing and the emergence of polymyxin resistance with polymyxin B and chloramphenicol combinations used against New Delhi metallo-β-lactamase (NDM)-producing MDR Klebsiella pneumoniae.

Methods Four NDM-producing K. pneumoniae strains were employed. The presence of genes conferring resistance to chloramphenicol was examined by PCR. Time–kill studies (inocula ∼106 cfu/mL) were conducted using various clinically achievable concentrations of each antibiotic (range: polymyxin B, 0.5–2 mg/L; chloramphenicol, 4–32 mg/L), with real-time population analysis profiles documented at baseline and 24 h. The microbiological response was examined using the log change method and pharmacodynamic modelling in conjunction with scanning electron microscopy (SEM).

Results Multiple genes coding for efflux pumps involved in chloramphenicol resistance were present in all strains. Polymyxin B monotherapy at all concentrations produced rapid bacterial killing followed by rapid regrowth with the emergence of polymyxin resistance; chloramphenicol monotherapy was largely ineffective. Combination therapy significantly delayed regrowth, with synergy observed in 25 out of 28 cases at both 6 and 24 h; at 24 h, no viable bacterial cells were detected in 15 out of 28 cases with various combinations across all strains. No polymyxin-resistant bacteria were detected with combination therapy. These results were supported by pharmacodynamic modelling. SEM revealed significant morphological changes following treatment with polymyxin B both alone and in combination.

Conclusions The combination of polymyxin B and chloramphenicol used against NDM-producing MDR K. pneumoniae substantially enhanced bacterial killing and suppressed the emergence of polymyxin resistance.
Keyword Synergy
New Delhi metallo-b-lactamase
K. pneumoniae
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Advance Access Publication

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
Official 2016 Collection
Institute for Molecular Bioscience - Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 13 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 16 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Tue, 21 Jul 2015, 00:47:55 EST by Susan Allen on behalf of Institute for Molecular Bioscience