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Omadacycline pharmacokinetics/pharmacodynamics and efficacy against multidrug-resistant Mycobacterium tuberculosis in the hollow fiber system model.
Singh, Sanjay; Gumbo, Tawanda; Boorgula, Gunavanthi D; Thomas, Tania A; Philley, Julie V; Srivastava, Shashikant.
Afiliação
  • Singh S; Department of Medicine, School of Medicine, University of Texas at Tyler, Tyler, Texas, USA.
  • Gumbo T; Quantitative Preclinical and Clinical Sciences Department, Praedicare Inc., Dallas, Texas, USA.
  • Boorgula GD; Hollow Fiber System and Experimental Therapeutics Laboratories, Praedicare Inc., Dallas, Texas, USA.
  • Thomas TA; Department of Medicine, School of Medicine, University of Texas at Tyler, Tyler, Texas, USA.
  • Philley JV; Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, Virginia, USA.
  • Srivastava S; Section of Pulmonary and Critical Care, School of Medicine, University of Texas at Tyler, Tyler, Texas, USA.
Antimicrob Agents Chemother ; 68(2): e0108023, 2024 Feb 07.
Article em En | MEDLINE | ID: mdl-38131673
ABSTRACT
Seventy-five years ago, first-generation tetracyclines demonstrated limited efficacy in the treatment of tuberculosis but were more toxic than efficacious. We performed a series of pharmacokinetic/pharmacodynamic (PK/PD) experiments with a potentially safer third-generation tetracycline, omadacycline, for the treatment of multidrug-resistant tuberculosis (MDR-TB). Mycobacterium tuberculosis (Mtb) H37Rv and an MDR-TB clinical strain (16D) were used in the minimum inhibitory concentration (MIC) and static concentration-response studies in test tubes, followed by a PK/PD study using the hollow fiber system model of TB (HFS-TB) that examined six human-like omadacycline doses. The inhibitory sigmoid maximal effect (Emax) model and Monte Carlo experiments (MCEs) were used for data analysis and clinical dose-finding, respectively. The omadacycline MIC for both Mtb H37Rv and MDR-TB clinical strain was 16 mg/L but dropped to 4 mg/L with daily drug supplementation to account for omadacycline degradation. The Mycobacteria Growth Indicator Tube MIC was 2 mg/L. In the test tubes, omadacycline killed 4.39 log10 CFU/mL in 7 days. On Day 28 of the HFS-TB study, the Emax was 4.64 log10 CFU/mL, while exposure mediating 50% of Emax (EC50) was an area under the concentration-time curve to MIC (AUC0-24/MIC) ratio of 22.86. This translates to PK/PD optimal exposure or EC80 as AUC0-24/MIC of 26.93. The target attainment probability of the 300-mg daily oral dose was 90% but fell at MIC ≧4 mg/L. Omadacycline demonstrated efficacy and potency against both drug-susceptible and MDR-TB. Further studies are needed to identify the omadacycline effect in combination therapy for the treatment of both drug-susceptible and MDR-TB.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tuberculose Resistente a Múltiplos Medicamentos / Mycobacterium tuberculosis Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tuberculose Resistente a Múltiplos Medicamentos / Mycobacterium tuberculosis Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article