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Pharmacokinetics-Pharmacodynamics of CB-618 in Combination with Cefepime, Ceftazidime, Ceftolozane, or Meropenem: the Pharmacological Basis for a Stand-Alone ß-Lactamase Inhibitor.
Ambrose, Paul G; VanScoy, Brian D; Trang, Michael; McCauley-Miller, Jennifer; Conde, Haley; Bhavnani, Sujata M; Alexander, Dylan C; Friedrich, Lawrence V.
Afiliação
  • Ambrose PG; Institute for Clinical Pharmacodynamics, Schenectady, New York, USA PAmbrose@ICPD.com.
  • VanScoy BD; Institute for Clinical Pharmacodynamics, Schenectady, New York, USA.
  • Trang M; Institute for Clinical Pharmacodynamics, Schenectady, New York, USA.
  • McCauley-Miller J; Institute for Clinical Pharmacodynamics, Schenectady, New York, USA.
  • Conde H; Institute for Clinical Pharmacodynamics, Schenectady, New York, USA.
  • Bhavnani SM; Institute for Clinical Pharmacodynamics, Schenectady, New York, USA.
  • Alexander DC; Merck and Co., Kenilworth, New Jersey, USA.
  • Friedrich LV; Merck and Co., Kenilworth, New Jersey, USA.
Article em En | MEDLINE | ID: mdl-28947474
A major challenge in treating patients is the selection of the "right" antibiotic regimen. Given that the optimal ß-lactam/ß-lactamase inhibitor pair is dependent upon the spectrum of ß-lactamase enzymes produced and the frequency of resistance to the ß-lactamase inhibitor, it might be useful if a stand-alone were available for the clinician to pair with the "right" ß-lactam rather than only in a fixed combination. We describe herein a one-compartment in vitro infection model studies conducted to identify the magnitudes of the pharmacokinetic-pharmacodynamic (PK-PD) index for a ß-lactamase inhibitor, CB-618, that would restore the activity of four ß-lactam partner agents (cefepime, ceftazidime, ceftolozane, and meropenem) with various doses (1 or 2 g) and dosing intervals (8 or 12 h). The challenge panel included Klebsiella pneumoniae (n = 5), Escherichia coli (n = 2), and Enterobacter cloacae (n = 1) strains, which produced a wide variety of ß-lactamase enzymes (AmpC, CTXM-15, KPC-2, KPC-3, FOX-5, OXA-1/30, OXA-48, SHV-1, SHV-11, SHV-27, and TEM-1). Free-drug human concentration-time profiles were simulated for each agent, and specimens were collected for drug concentration and bacterial density determinations. CB-618 restored the activity of each ß-lactam partner. The magnitudes of the CB-618 ratio of the area under the concentration-time curve from 0 to 24 h to the MIC (i.e., the AUC/MIC ratio) associated with net bacterial stasis and 1- and 2-log10 CFU/ml reductions from baseline at 24 h were 11.2, 32.9, and 136.3, respectively. These data may provide a PK-PD basis for the development of a stand-alone ß-lactamase inhibitor.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ceftazidima / Cefalosporinas / Tienamicinas / Inibidores de beta-Lactamases / Antibacterianos Limite: Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ceftazidima / Cefalosporinas / Tienamicinas / Inibidores de beta-Lactamases / Antibacterianos Limite: Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article