Linezolid dose that maximizes sterilizing effect while minimizing toxicity and resistance emergence for tuberculosis

Shashikant Srivastava, Gesham Magombedze, Thearith Koeuth, Carleton Sherman, Jotam G. Pasipanodya, Prithvi Raj, Edward Wakeland, Devyani Deshpande, Tawanda Gumbo

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Linezolid has an excellent sterilizing effect in tuberculosis patients but high adverse event rates. The dose that would maximize efficacy and minimize toxicity is unknown. We performed linezolid dose-effect and dose-scheduling studies in the hollow fiber system model of tuberculosis (HFS-TB) for sterilizing effect. HFS-TB units were treated with several doses to mimic human-like linezolid intrapulmonary pharmacokinetics and repetitively sampled for drug concentration, total bacterial burden, linezolid-resistant subpopulations, and RNA sequencing over 2 months. Linezolid-resistant isolates underwent whole-genome sequencing. The expression of genes encoding efflux pumps in the first 1 to 2 weeks revealed the same exposure-response patterns as the linezolid-resistant subpopulation. Linezolid-resistant isolates from the 2nd month of therapy revealed mutations in several efflux pump/transporter genes and a LuxR-family transcriptional regulator. Linezolid sterilizing effect was linked to the ratio of unbound 0- to 24-h area under the concentration-time curve (AUC0–24) to MIC. Optimal microbial kill was achieved at an AUC0–24/MIC ratio of 119. The optimal sterilizing effect dose for clinical use was identified using Monte Carlo simulations. Clinical doses of 300 and 600 mg/day (or double the dose every other day) achieved this target in 87% and >99% of 10,000 patients, respectively. The susceptibility breakpoint identified was 2 mg/liter. The simulations identified that a 300-mg/day dose did not achieve AUC0–24s associated with linezolid toxicity, while 600 mg/day achieved those AUC0–24s in <20% of subjects. The linezolid dose of 300 mg/day performed well and should be compared to 600 mg/day or 1,200 mg every other day in clinical trials.

Original languageEnglish (US)
Article numbere00751
JournalAntimicrobial Agents and Chemotherapy
Volume61
Issue number8
DOIs
StatePublished - Aug 1 2017

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Linezolid
Tuberculosis
RNA Sequence Analysis

Keywords

  • Efflux pump regulators
  • Efflux pumps
  • Mutations
  • Optimal dose
  • RNA sequencing
  • Whole-genome sequencing

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Linezolid dose that maximizes sterilizing effect while minimizing toxicity and resistance emergence for tuberculosis. / Srivastava, Shashikant; Magombedze, Gesham; Koeuth, Thearith; Sherman, Carleton; Pasipanodya, Jotam G.; Raj, Prithvi; Wakeland, Edward; Deshpande, Devyani; Gumbo, Tawanda.

In: Antimicrobial Agents and Chemotherapy, Vol. 61, No. 8, e00751, 01.08.2017.

Research output: Contribution to journalArticle

Srivastava, Shashikant ; Magombedze, Gesham ; Koeuth, Thearith ; Sherman, Carleton ; Pasipanodya, Jotam G. ; Raj, Prithvi ; Wakeland, Edward ; Deshpande, Devyani ; Gumbo, Tawanda. / Linezolid dose that maximizes sterilizing effect while minimizing toxicity and resistance emergence for tuberculosis. In: Antimicrobial Agents and Chemotherapy. 2017 ; Vol. 61, No. 8.
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abstract = "Linezolid has an excellent sterilizing effect in tuberculosis patients but high adverse event rates. The dose that would maximize efficacy and minimize toxicity is unknown. We performed linezolid dose-effect and dose-scheduling studies in the hollow fiber system model of tuberculosis (HFS-TB) for sterilizing effect. HFS-TB units were treated with several doses to mimic human-like linezolid intrapulmonary pharmacokinetics and repetitively sampled for drug concentration, total bacterial burden, linezolid-resistant subpopulations, and RNA sequencing over 2 months. Linezolid-resistant isolates underwent whole-genome sequencing. The expression of genes encoding efflux pumps in the first 1 to 2 weeks revealed the same exposure-response patterns as the linezolid-resistant subpopulation. Linezolid-resistant isolates from the 2nd month of therapy revealed mutations in several efflux pump/transporter genes and a LuxR-family transcriptional regulator. Linezolid sterilizing effect was linked to the ratio of unbound 0- to 24-h area under the concentration-time curve (AUC0–24) to MIC. Optimal microbial kill was achieved at an AUC0–24/MIC ratio of 119. The optimal sterilizing effect dose for clinical use was identified using Monte Carlo simulations. Clinical doses of 300 and 600 mg/day (or double the dose every other day) achieved this target in 87{\%} and >99{\%} of 10,000 patients, respectively. The susceptibility breakpoint identified was 2 mg/liter. The simulations identified that a 300-mg/day dose did not achieve AUC0–24s associated with linezolid toxicity, while 600 mg/day achieved those AUC0–24s in <20{\%} of subjects. The linezolid dose of 300 mg/day performed well and should be compared to 600 mg/day or 1,200 mg every other day in clinical trials.",
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