Concentration-Dependent Synergy and Antagonism of Linezolid and Moxifloxacin in the Treatment of Childhood Tuberculosis

The Dynamic Duo

Devyani Deshpande, Shashikant Srivastava, Eric Nuermberger, Jotam G. Pasipanodya, Soumya Swaminathan, Tawanda Gumbo

Research output: Contribution to journalArticle

Abstract

Background. No treatment regimens have been specifically designed for children, in whom tuberculosis is predominantly intracellular. Given their activity as monotherapy and their ability to penetrate many diseased anatomic sites that characterize disseminated tuberculosis, linezolid and moxifloxacin could be combined to form a regimen for this need. Methods. We examined microbial kill of intracellular Mycobacterium tuberculosis (Mtb) by the combination of linezolid and moxifloxacin multiple exposures in a 7-by-7 mathematical matrix. We then used the hollow fiber system (HFS) model of intracellular tuberculosis to identify optimal dose schedules and exposures of moxifloxacin and linezolid in combination. We mimicked pediatric half-lives and concentrations achieved by each drug. We sampled the peripheral compartment on days 0, 7, 14, 21, and 28 for Mtb quantification, and compared the slope of microbial kill of Mtb by these regimens to the standard regimen of isoniazid, rifampin, and pyrazinamide, based on exponential decline regression. Results. The full exposure-response surface identified linezolid-moxifloxacin zones of synergy, antagonism, and additivity. A regimen based on each of these zones was then used in the HFS model, with observed half-lives of 4.08 ± 0.66 for linezolid and 3.80 ± 1.34 hours for moxifloxacin. The kill rate constant was 0.060 ± 0.012 per day with the moxifloxacin-linezolid regimen in the additivity zone vs 0.083 ± 0.011 per day with standard therapy, translating to a bacterial burden half-life of 11.52 days vs 8.53 days, respectively. Conclusions. We identified doses and dose schedules of a linezolid and moxifloxacin backbone regimen that could be highly efficacious in disseminated tuberculosis in children.

Original languageEnglish (US)
Pages (from-to)S88-S94
JournalClinical Infectious Diseases
Volume63
DOIs
StatePublished - Nov 1 2016

Fingerprint

Linezolid
Tuberculosis
Mycobacterium tuberculosis
Therapeutics
Appointments and Schedules
Pyrazinamide
Isoniazid
Rifampin
moxifloxacin
Half-Life

Keywords

  • additivity
  • Bliss independence
  • disseminated tuberculosis
  • exposure-response surface
  • hollow fiber system model

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases

Cite this

Concentration-Dependent Synergy and Antagonism of Linezolid and Moxifloxacin in the Treatment of Childhood Tuberculosis : The Dynamic Duo. / Deshpande, Devyani; Srivastava, Shashikant; Nuermberger, Eric; Pasipanodya, Jotam G.; Swaminathan, Soumya; Gumbo, Tawanda.

In: Clinical Infectious Diseases, Vol. 63, 01.11.2016, p. S88-S94.

Research output: Contribution to journalArticle

Deshpande, Devyani ; Srivastava, Shashikant ; Nuermberger, Eric ; Pasipanodya, Jotam G. ; Swaminathan, Soumya ; Gumbo, Tawanda. / Concentration-Dependent Synergy and Antagonism of Linezolid and Moxifloxacin in the Treatment of Childhood Tuberculosis : The Dynamic Duo. In: Clinical Infectious Diseases. 2016 ; Vol. 63. pp. S88-S94.
@article{30ac7b0f95614beb952fd6a1dd5a7dc9,
title = "Concentration-Dependent Synergy and Antagonism of Linezolid and Moxifloxacin in the Treatment of Childhood Tuberculosis: The Dynamic Duo",
abstract = "Background. No treatment regimens have been specifically designed for children, in whom tuberculosis is predominantly intracellular. Given their activity as monotherapy and their ability to penetrate many diseased anatomic sites that characterize disseminated tuberculosis, linezolid and moxifloxacin could be combined to form a regimen for this need. Methods. We examined microbial kill of intracellular Mycobacterium tuberculosis (Mtb) by the combination of linezolid and moxifloxacin multiple exposures in a 7-by-7 mathematical matrix. We then used the hollow fiber system (HFS) model of intracellular tuberculosis to identify optimal dose schedules and exposures of moxifloxacin and linezolid in combination. We mimicked pediatric half-lives and concentrations achieved by each drug. We sampled the peripheral compartment on days 0, 7, 14, 21, and 28 for Mtb quantification, and compared the slope of microbial kill of Mtb by these regimens to the standard regimen of isoniazid, rifampin, and pyrazinamide, based on exponential decline regression. Results. The full exposure-response surface identified linezolid-moxifloxacin zones of synergy, antagonism, and additivity. A regimen based on each of these zones was then used in the HFS model, with observed half-lives of 4.08 ± 0.66 for linezolid and 3.80 ± 1.34 hours for moxifloxacin. The kill rate constant was 0.060 ± 0.012 per day with the moxifloxacin-linezolid regimen in the additivity zone vs 0.083 ± 0.011 per day with standard therapy, translating to a bacterial burden half-life of 11.52 days vs 8.53 days, respectively. Conclusions. We identified doses and dose schedules of a linezolid and moxifloxacin backbone regimen that could be highly efficacious in disseminated tuberculosis in children.",
keywords = "additivity, Bliss independence, disseminated tuberculosis, exposure-response surface, hollow fiber system model",
author = "Devyani Deshpande and Shashikant Srivastava and Eric Nuermberger and Pasipanodya, {Jotam G.} and Soumya Swaminathan and Tawanda Gumbo",
year = "2016",
month = "11",
day = "1",
doi = "10.1093/cid/ciw473",
language = "English (US)",
volume = "63",
pages = "S88--S94",
journal = "Clinical Infectious Diseases",
issn = "1058-4838",
publisher = "Oxford University Press",

}

TY - JOUR

T1 - Concentration-Dependent Synergy and Antagonism of Linezolid and Moxifloxacin in the Treatment of Childhood Tuberculosis

T2 - The Dynamic Duo

AU - Deshpande, Devyani

AU - Srivastava, Shashikant

AU - Nuermberger, Eric

AU - Pasipanodya, Jotam G.

AU - Swaminathan, Soumya

AU - Gumbo, Tawanda

PY - 2016/11/1

Y1 - 2016/11/1

N2 - Background. No treatment regimens have been specifically designed for children, in whom tuberculosis is predominantly intracellular. Given their activity as monotherapy and their ability to penetrate many diseased anatomic sites that characterize disseminated tuberculosis, linezolid and moxifloxacin could be combined to form a regimen for this need. Methods. We examined microbial kill of intracellular Mycobacterium tuberculosis (Mtb) by the combination of linezolid and moxifloxacin multiple exposures in a 7-by-7 mathematical matrix. We then used the hollow fiber system (HFS) model of intracellular tuberculosis to identify optimal dose schedules and exposures of moxifloxacin and linezolid in combination. We mimicked pediatric half-lives and concentrations achieved by each drug. We sampled the peripheral compartment on days 0, 7, 14, 21, and 28 for Mtb quantification, and compared the slope of microbial kill of Mtb by these regimens to the standard regimen of isoniazid, rifampin, and pyrazinamide, based on exponential decline regression. Results. The full exposure-response surface identified linezolid-moxifloxacin zones of synergy, antagonism, and additivity. A regimen based on each of these zones was then used in the HFS model, with observed half-lives of 4.08 ± 0.66 for linezolid and 3.80 ± 1.34 hours for moxifloxacin. The kill rate constant was 0.060 ± 0.012 per day with the moxifloxacin-linezolid regimen in the additivity zone vs 0.083 ± 0.011 per day with standard therapy, translating to a bacterial burden half-life of 11.52 days vs 8.53 days, respectively. Conclusions. We identified doses and dose schedules of a linezolid and moxifloxacin backbone regimen that could be highly efficacious in disseminated tuberculosis in children.

AB - Background. No treatment regimens have been specifically designed for children, in whom tuberculosis is predominantly intracellular. Given their activity as monotherapy and their ability to penetrate many diseased anatomic sites that characterize disseminated tuberculosis, linezolid and moxifloxacin could be combined to form a regimen for this need. Methods. We examined microbial kill of intracellular Mycobacterium tuberculosis (Mtb) by the combination of linezolid and moxifloxacin multiple exposures in a 7-by-7 mathematical matrix. We then used the hollow fiber system (HFS) model of intracellular tuberculosis to identify optimal dose schedules and exposures of moxifloxacin and linezolid in combination. We mimicked pediatric half-lives and concentrations achieved by each drug. We sampled the peripheral compartment on days 0, 7, 14, 21, and 28 for Mtb quantification, and compared the slope of microbial kill of Mtb by these regimens to the standard regimen of isoniazid, rifampin, and pyrazinamide, based on exponential decline regression. Results. The full exposure-response surface identified linezolid-moxifloxacin zones of synergy, antagonism, and additivity. A regimen based on each of these zones was then used in the HFS model, with observed half-lives of 4.08 ± 0.66 for linezolid and 3.80 ± 1.34 hours for moxifloxacin. The kill rate constant was 0.060 ± 0.012 per day with the moxifloxacin-linezolid regimen in the additivity zone vs 0.083 ± 0.011 per day with standard therapy, translating to a bacterial burden half-life of 11.52 days vs 8.53 days, respectively. Conclusions. We identified doses and dose schedules of a linezolid and moxifloxacin backbone regimen that could be highly efficacious in disseminated tuberculosis in children.

KW - additivity

KW - Bliss independence

KW - disseminated tuberculosis

KW - exposure-response surface

KW - hollow fiber system model

UR - http://www.scopus.com/inward/record.url?scp=84994559571&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84994559571&partnerID=8YFLogxK

U2 - 10.1093/cid/ciw473

DO - 10.1093/cid/ciw473

M3 - Article

VL - 63

SP - S88-S94

JO - Clinical Infectious Diseases

JF - Clinical Infectious Diseases

SN - 1058-4838

ER -