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

Rahim, Nusaibah Abdul; Cheah, Soon-Ee; Johnson, Matthew D.; Yu, Heidi H.; Sidjabat, Hanna E.; Boyce, John D.; Butler, Mark S.; Cooper, Matthew A.; Fu, Jianzhong; Paterson, David L.; Nation, Roger L.; Bergen, Phillip J.; Velkov, Tony; Li, Jian

doi:10.1093/jac/dkv135

Cited by 77 publications

(58 citation statements)

References 41 publications

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“…3). Similar outer membrane changes have been observed in Escherichia coli [35], Pseudomonas aeruginosa [35] and K. pneumoniae [36] following treatment with PMB. Treatment with meropenem alone resulted in only rounding of the bacterial cell, which has also been observed in P. aeruginosa [37].…”

Section: Discussionsupporting

confidence: 78%

Polymyxin B in combination with meropenem against carbapenemase-producing Klebsiella pneumoniae: pharmacodynamics and morphological changes

Sharma

Patel

Abboud

et al. 2017

International Journal of Antimicrobial Agents

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Combination therapy provides a useful therapeutic approach to overcome resistance until new antibiotics become available. In this study, the pharmacodynamics, including the morphological effects, of polymyxin B (PMB) and meropenem alone and in combination against KPC-producing Klebsiella pneumoniae clinical isolates was examined. Ten clinical isolates were obtained from patients undergoing treatment for mediastinitis. KPCs were identified and MICs were measured using microbroth dilution. Time–kill studies were conducted over 24 h with PMB (0.5–16 mg/L) and meropenem (20–120 mg/L) alone or in combination against an initial inoculum of ca. 106 CFU/mL. Scanning electron microscopy (SEM) was employed to analyse changes in bacterial morphology after treatment, and the log change method was used to quantify the pharmacodynamic effect. All isolates harboured the blaKPC-2 gene and were resistant to meropenem (MICs ≥8 mg/L). Clinically relevant PMB concentrations (0.5, 1.0 and 2.0 mg/L) in combination with meropenem were synergistic against all isolates except BRKP28 (polymyxin- and meropenem-resistant, both MICs >128 mg/L). All PMB and meropenem concentrations in combination were bactericidal against polymyxin-susceptible isolates with meropenem MICs ≤16 mg/L. SEM revealed extensive morphological changes following treatment with PMB in combination with meropenem compared with the changes observed with each individual agent. Additionally, morphological changes decreased with increasing resistance profiles of the isolate, i.e. increasing meropenem MIC. These antimicrobial effects may not only be a summation of the effects due to each antibiotic but also a result of differential action that likely inhibits protective mechanisms in bacteria.

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Section: Discussionsupporting

confidence: 78%

Polymyxin B in combination with meropenem against carbapenemase-producing Klebsiella pneumoniae: pharmacodynamics and morphological changes

Sharma

Patel

Abboud

et al. 2017

International Journal of Antimicrobial Agents

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“…None of these residues was reported to participate in forming or maintaining the dimer architecture 8 . Therefore this relative conservation being retained under selection pressures suggests that it might be essential for virus survival and replication in vivo, especially virus-host first interaction as discussed previously by Li et al concerning R512 8 , R578 and K554 9 . We can further speculate that the dimerization of the P2 domain could be an evolutionary feature that aims to protect these digestion sites (R542, K544 and K554 as discussed earlier) that cannot be naturally mutated due their functional importance.…”

Section: Discussionmentioning

confidence: 69%

“…Domain P2 forms a protruding spike from the shell, is responsible for cell-attachment and contains the dominant neutralizing epitopes 9,12,19,20 making it thus the most exposed region to the gastrointestinal juice.…”

Section: Discussionmentioning

confidence: 99%

Dimerization: A structural feature for the protection of Hepatitis E virus capsid protein against trypsinization

Wei¹,

Meng²,

Behloul³

et al. 2018

Journal of Hepatology

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“…67,68 In brief, one colony of P. aeruginosa FADDI-PA066 was randomly selected and used to prepare a biofilm culture of which 10 mL of log-phase cultures (at ∼10 8 CFU/mL) in CAMHB were obtained. The tubes were treated with 128 mg/L colistin or 16 mg/L octapeptin A 3 and incubated for 1 h at 37 °C followed by centrifugation at 3220 g for 10 min.…”

Section: Methodsmentioning

confidence: 99%

“…Bacterial cells were fixed with 2.5% glutaraldehyde, washed, and imaged as described in detail. 67,68 …”

Section: Methodsmentioning

confidence: 99%

Sputum Active Polymyxin Lipopeptides: Activity against Cystic Fibrosis Pseudomonas aeruginosa Isolates and Their Interactions with Sputum Biomolecules

et al. 2018

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The mucoid biofilm mode of growth of Pseudomonas aeruginosa (P. aeruginosa) in the lungs of cystic fibrosis patients makes eradication of infections with antibiotic therapy very difficult. The lipopeptide antibiotics polymyxin B and colistin are currently the last-resort therapies for infections caused by multidrug-resistant P. aeruginosa. In the present study, we investigated the antibacterial activity of a series of polymyxin lipopeptides (polymyxin B, colistin, FADDI-003, octapeptin A3, and polymyxin A2) against a panel of polymyxin-susceptible and polymyxin-resistant P. aeruginosa cystic fibrosis isolates grown under planktonic or biofilm conditions in artificial sputum and their interactions with sputum component biomolecules. In sputum media under planktonic conditions, the lipopeptides FADDI-003 and octapeptin A3 displayed very promising activity against the polymyxin-resistant isolate FADDI-PA066 (polymyxin B minimum inhibitory concentration (MIC) = 32 mg/L), while retaining their activity against the polymyxin-sensitive strains FADDI-PA021 (polymyxin B MIC = 1 mg/L) and FADDI-PA020 (polymyxin B MIC = 2 mg/L). Polymyxin A2 was only effective against the polymyxin-sensitive isolates. However, under biofilm growth conditions, the hydrophobic lipopeptide FADDI-003 was inactive compared to the more hydrophilic lipopeptides, octapeptin A3, polymyxin A2, polymyxin B, and colistin. Transmission electron micrographs revealed octapeptin A3 caused reduction in the cell numbers in biofilm as well as biofilm disruption/“antibiofilm” activity. We therefore assessed the interactions of the lipopeptides with the component sputum biomolecules, mucin, deoxyribonucleic acid (DNA), surfactant, F-actin, lipopolysaccharide, and phospholipids. We observed the general trend that sputum biomolecules reduce lipopeptide antibacterial activity. Collectively, our data suggests that, in the airways, lipopeptide binding to component sputum biomolecules may reduce antibacterial efficacy and is dependent on the physicochemical properties of the lipopeptide.

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Synergistic killing of NDM-producing MDRKlebsiella pneumoniaeby two ‘old’ antibiotics—polymyxin B and chloramphenicol

Abstract: 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.

Cited by 77 publications

References 41 publications

Polymyxin B in combination with meropenem against carbapenemase-producing Klebsiella pneumoniae: pharmacodynamics and morphological changes

Polymyxin B in combination with meropenem against carbapenemase-producing Klebsiella pneumoniae: pharmacodynamics and morphological changes

Dimerization: A structural feature for the protection of Hepatitis E virus capsid protein against trypsinization

Sputum Active Polymyxin Lipopeptides: Activity against Cystic Fibrosis Pseudomonas aeruginosa Isolates and Their Interactions with Sputum Biomolecules

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