Journal
INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS
Volume 56, Issue 2, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.ijantimicag.2020.106061
Keywords
Polymyxin B; Chloramphenicol; New Delhi metallo-beta-lactamase; Klebsiella pneumoniae; Systems pharmacology; Transcriptomics
Funding
- Australian National Health and Medical Research Council (NHMRC) [APP1046561]
- National Institute of Allergy and Infectious Diseases of the National Institutes of Health [R01 AI132681]
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The combination of polymyxins and chloramphenicol possesses synergistic killing activity against New Delhi metallo-beta-lactamase (NDM)-producing Klebsiella pneumoniae. This systems study examined the transcriptomic responses to the polymyxin/chloramphenicol combination in clinical NDM-producing K. pneumoniae isolate S01. Klebsiella pneumoniae S01 (initial inoculum similar to 10(8) CFU/mL) was treated with polymyxin B (1 mg/L, continuous infusion) or chloramphenicol [maximum concentration (C-max) = 8 mg/L, half-life (t(1/2)) = 4 h], alone or in combination, using an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model to mimic their pharmacokinetics in patients. Transcriptomic profiles of bacterial samples collected at 0, 0.25, 1, 4 and 24 h were examined using RNA sequencing (RNA-Seq). Chloramphenicol monotherapy significantly increased the expression of genes involved in ribosomal synthesis across the entire 24-h treatment, reflective of chloramphenicol-mediated inhibition of protein synthesis. The effect of polymyxin B was rapid and no major pathways were perturbed at later time points (4 h and 24 h). Combination treatment yielded the highest number of differentially expressed genes, including a large number observed following chloramphenicol monotherapy, in particular carbohydrate, nucleotide, amino acid and cell wall metabolism. Notably, chloramphenicol alone and in combination with polymyxin B significantly inhibited the expression of the arn operon that is responsible for lipid A modification and polymyxin resistance. These results indicate that the polymyxin/chloramphenicol combination displayed persistent transcriptomic responses over 24 h mainly on cell envelope synthesis and metabolism of carbohydrates, nucleotides and amino acids. (C) 2020 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
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