2021
DOI: 10.1002/cpt.2197
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Evaluation Strategies for Triple‐Drug Combinations against Carbapenemase‐Producing Klebsiella Pneumoniae in an In Vitro Hollow‐Fiber Infection Model

Abstract: Mounting antimicrobial resistance to carbapenemase-producing Klebsiella pneumoniae (CPKP) highlights the need to optimize currently available treatment options. The objective of this study was to explore alternative dosing strategies that limit the emergence of resistance to preserve the utility of last-line antibiotics by: (i) evaluating the pharmacodynamic (PD) killing activity of simulated humanized exposures to monotherapy and two-drug and three-drug combinations against CPKP bacterial isolates with differ… Show more

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Cited by 11 publications
(7 citation statements)
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“…minimize emergence of resistance using dynamic in vitro models of infection. [16][17][18][19] Chloramphenicol (CHL) is a broad-spectrum antibiotic that inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit, was approved for clinical use in the late 1940s, and was the first antibiotic to be manufactured synthetically on a large scale. 20 These drugs were abandoned due to their toxicities: nephrotoxicity for polymyxins and aplastic anemia for CHL.…”
Section: How Might This Change Drug Discovery Development And/or Ther...mentioning
confidence: 99%
See 1 more Smart Citation
“…minimize emergence of resistance using dynamic in vitro models of infection. [16][17][18][19] Chloramphenicol (CHL) is a broad-spectrum antibiotic that inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit, was approved for clinical use in the late 1940s, and was the first antibiotic to be manufactured synthetically on a large scale. 20 These drugs were abandoned due to their toxicities: nephrotoxicity for polymyxins and aplastic anemia for CHL.…”
Section: How Might This Change Drug Discovery Development And/or Ther...mentioning
confidence: 99%
“…Given that polymyxin B (PMB), an old antibiotic, is still effective as a last line agent against infections caused by CRKP, there is a need to identify and develop novel PMB‐based combination therapies to conserve its utility 14,15 . Our group has previously explored and evaluated PMB‐based double and triple combination therapies that maintain efficacy and minimize emergence of resistance using dynamic in vitro models of infection 16–19 . Chloramphenicol (CHL) is a broad‐spectrum antibiotic that inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit, was approved for clinical use in the late 1940s, and was the first antibiotic to be manufactured synthetically on a large scale 20 .…”
Section: Introductionmentioning
confidence: 99%
“…Double combinations that utilize a polymyxin and fosfomycin have also been investigated in vitro against polymyxin-resistant KPCKP, and the combination was able to achieve synergy in time-killing experiments (albeit at high drug concentrations) and a hollow-fiber infection model [35,36]. In vitro dynamic model [33] In vivo rabbit osteomyelitis model [32] (meropenem) + colistin + gentamicin In vivo rabbit osteomyelitis model [32] (meropenem) + polymyxin B + fosfomycin In vitro dynamic model [37] (meropenem) + colistin + tigecycline In vitro dynamic model [33] (meropenem) + colistin and/or tigecycline and/or gentamicin Retrospective clinical [34] (meropenem) + (amikacin)…”
Section: Klebsiella Pneumoniae 41 K Pneumoniae Carbapenemase-producin...mentioning
confidence: 99%
“…In vivo murine thigh model [42] Retrospective clinical [43,44] NDMKP (meropenem) + tigecycline In vitro dynamic model [45] (meropenem) + fosfomycin + polymyxin B In vitro dynamic model [37] (fosfomycin) + colistin In vitro dynamic model [46] (polymyxin B) + amikacin + aztreonam In vitro dynamic model [47] ˆDrugs were determined to be inactive if the pathogens' MIC was above the CLSI breakpoint for susceptibility, if available. Polymyxin MICs of 2 or higher were considered inactive.…”
Section: Klebsiella Pneumoniae 41 K Pneumoniae Carbapenemase-producin...mentioning
confidence: 99%
“…Most of the work done on the HFIM has focused on bacteria and antimicrobial testing. 11,[13][14][15] Although comprehensive literature on the use of the HFIM for performance evaluation of antimicrobial compounds exist, [16][17][18][19][20] the current literature about the applications of the HFIM to study viral infections is still lacking. This review therefore focuses on the applications of the HFIM in viral infection studies.…”
Section: Introductionmentioning
confidence: 99%