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Evaluation Strategies for Triple-Drug Combinations against Carbapenemase-Producing Klebsiella Pneumoniae in an In Vitro Hollow-Fiber Infection Model
Garcia, Estefany; Diep, John K; Sharma, Rajnikant; Hanafin, Patrick O; Abboud, Cely S; Kaye, Keith S; Li, Jian; Velkov, Tony; Rao, Gauri G.
Afiliação
  • Garcia, Estefany; University of North Carolina. UNC Eshelman School of Pharmacy. Chapel Hill. US
  • Diep, John K; University of North Carolina. UNC Eshelman School of Pharmacy. Chapel Hill. US
  • Sharma, Rajnikant; University of North Carolina. UNC Eshelman School of Pharmacy,. Chapel Hill. BR
  • Hanafin, Patrick O; University of North Carolina. UNC Eshelman School of Pharmacy. Chapel Hill. US
  • Abboud, Cely S; Instituto Dante Pazzanese de Cardiologia. São Paulo. BR
  • Kaye, Keith S; University of Michigan Medical School. Division of Infectious Diseases, Department of Internal Medicine. Ann Arbor. US
  • Li, Jian; Monash University. Biomedicine Discovery Institute, Department of Microbiology. Clayton. AU
  • Velkov, Tony; University of Melbourne. Department of Pharmacology and Therapeutics. Melbourne. AU
  • Rao, Gauri G; University of North Carolina. Eshelman School of Pharmacy. Chapel Hill. US
Clin. pharmacol. ther ; Clin. pharmacol. ther;109(4): 160-212, Apr. 2021. graf, tab
Article em En | SES-SP, CONASS, SESSP-IDPCPROD, SES-SP | ID: biblio-1177204
Biblioteca responsável: BR79.1
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 different resistance mechanisms; and (ii) optimizing polymyxin B (PMB) exposure simulated in the three-drug combination regimens to maximize the killing activity. Two CPKP clinical isolates (BAA2146 (NDM-1) and BRKP76 (KPC-2)) were evaluated over 168 hours using a hollow-fiber infection model simulating clinically relevant PMB, fosfomycin, and meropenem dosing regimens. PMB-based three-drug combinations were further optimized by varying the initial exposure (0­24 hours) or maintenance dose received over the duration of treatment. The area under the bacterial load-versus-time curve (AUCFU) was used to determine PD activity. Overall reductions in PMB exposure ranged from 2 to 84%. BAA2146 and BRKP76 had median (range) AUCFUs of 11.0 (10.6­11.6) log10 CFU hour/mL and 7.08 (7.04­11.9) log10 CFU hour/mL, respectively. The PMB "front loaded" 2.5 mg/ kg/day + 0.5 mg/kg maintenance dose in combination with meropenem and fosfomycin was a promising regimen against BRKP76, with an overall reduction in PMB exposure of 56% while still eradicating the bacteria. Tailored triple combination therapy allows for the optimization of dose and treatment duration of last-line agents like PMB to achieve adequate drug exposure and appropriate PD activity while minimizing the emergence of resistance.
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Texto completo: 1 Coleções: 06-national / BR Base de dados: CONASS / SES-SP / SESSP-IDPCPROD Assunto principal: Combinação de Medicamentos / Klebsiella pneumoniae Idioma: En Revista: Clin. pharmacol. ther Ano de publicação: 2021 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 06-national / BR Base de dados: CONASS / SES-SP / SESSP-IDPCPROD Assunto principal: Combinação de Medicamentos / Klebsiella pneumoniae Idioma: En Revista: Clin. pharmacol. ther Ano de publicação: 2021 Tipo de documento: Article