Kinetic driver of antibacterial drugs against plasmodium falciparum and implications for clinical dosing

Emily Caton, Elizabeth Nenortas, Rahul P. Bakshi, Theresa A. Shapiro

Research output: Contribution to journalArticle

Abstract

Antibacterial drugs are an important component of malaria therapy. We studied the interactions of clindamycin, tetracycline, chloramphenicol, and ciprofloxacin against Plasmodium falciparum under static and dynamic conditions. In microtiter plate assays (static conditions), and as expected, parasites displayed the delayed death response characteristic for apicoplast-targeting drugs. However, rescue by isopentenyl pyrophosphate was variable, ranging from 2,700-fold for clindamycin to just 1.7-fold for ciprofloxacin, suggesting that ciprofloxacin has targets other than the apicoplast. We also examined the pharmacokinetic-pharmacodynamic relationships of these antibacterials in an in vitro glass hollow-fiber system that exposes parasites to dynamically changing drug concentrations. The same total dose and area under the concentration-time curve (AUC) of the drug was deployed either as a single short-lived high peak (bolus) or as a constant low concentration (infusion). All four antibacterials were unambiguously time-driven against malaria parasites: infusions had twice the efficacy of bolus regimens, for the same AUC. The time-dependent efficacy of ciprofloxacin against malaria is in contrast to its concentration-driven action against bacteria. In silico simulations of clinical dosing regimens and resulting pharmacokinetics revealed that current regimens do not maximize time above the MICs of these drugs. Our findings suggest that simple and rational changes to dosing may improve the efficacy of antibacterials against falciparum malaria.

Original languageEnglish (US)
Article numbere00416-19
JournalAntimicrobial agents and chemotherapy
Volume63
Issue number11
DOIs
StatePublished - Jan 1 2019

Fingerprint

Plasmodium falciparum
Ciprofloxacin
Apicoplasts
Malaria
Parasites
Pharmaceutical Preparations
Clindamycin
Pharmacokinetics
Falciparum Malaria
Chloramphenicol
Drug Delivery Systems
Tetracycline
Computer Simulation
Bacteria
Therapeutics

Keywords

  • Chemotherapy
  • Chloramphenicol
  • Ciprofloxacin
  • Clindamycin
  • Doxycycline
  • Malaria
  • Pharmacodynamics
  • Pharmacokinetics
  • PK/PD
  • Plasmodium falciparum
  • Tetracycline

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Kinetic driver of antibacterial drugs against plasmodium falciparum and implications for clinical dosing. / Caton, Emily; Nenortas, Elizabeth; Bakshi, Rahul P.; Shapiro, Theresa A.

In: Antimicrobial agents and chemotherapy, Vol. 63, No. 11, e00416-19, 01.01.2019.

Research output: Contribution to journalArticle

@article{0a59e12ae5f54e9e953b8b950e73745d,
title = "Kinetic driver of antibacterial drugs against plasmodium falciparum and implications for clinical dosing",
abstract = "Antibacterial drugs are an important component of malaria therapy. We studied the interactions of clindamycin, tetracycline, chloramphenicol, and ciprofloxacin against Plasmodium falciparum under static and dynamic conditions. In microtiter plate assays (static conditions), and as expected, parasites displayed the delayed death response characteristic for apicoplast-targeting drugs. However, rescue by isopentenyl pyrophosphate was variable, ranging from 2,700-fold for clindamycin to just 1.7-fold for ciprofloxacin, suggesting that ciprofloxacin has targets other than the apicoplast. We also examined the pharmacokinetic-pharmacodynamic relationships of these antibacterials in an in vitro glass hollow-fiber system that exposes parasites to dynamically changing drug concentrations. The same total dose and area under the concentration-time curve (AUC) of the drug was deployed either as a single short-lived high peak (bolus) or as a constant low concentration (infusion). All four antibacterials were unambiguously time-driven against malaria parasites: infusions had twice the efficacy of bolus regimens, for the same AUC. The time-dependent efficacy of ciprofloxacin against malaria is in contrast to its concentration-driven action against bacteria. In silico simulations of clinical dosing regimens and resulting pharmacokinetics revealed that current regimens do not maximize time above the MICs of these drugs. Our findings suggest that simple and rational changes to dosing may improve the efficacy of antibacterials against falciparum malaria.",
keywords = "Chemotherapy, Chloramphenicol, Ciprofloxacin, Clindamycin, Doxycycline, Malaria, Pharmacodynamics, Pharmacokinetics, PK/PD, Plasmodium falciparum, Tetracycline",
author = "Emily Caton and Elizabeth Nenortas and Bakshi, {Rahul P.} and Shapiro, {Theresa A.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1128/AAC.00416-19",
language = "English (US)",
volume = "63",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "11",

}

TY - JOUR

T1 - Kinetic driver of antibacterial drugs against plasmodium falciparum and implications for clinical dosing

AU - Caton, Emily

AU - Nenortas, Elizabeth

AU - Bakshi, Rahul P.

AU - Shapiro, Theresa A.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Antibacterial drugs are an important component of malaria therapy. We studied the interactions of clindamycin, tetracycline, chloramphenicol, and ciprofloxacin against Plasmodium falciparum under static and dynamic conditions. In microtiter plate assays (static conditions), and as expected, parasites displayed the delayed death response characteristic for apicoplast-targeting drugs. However, rescue by isopentenyl pyrophosphate was variable, ranging from 2,700-fold for clindamycin to just 1.7-fold for ciprofloxacin, suggesting that ciprofloxacin has targets other than the apicoplast. We also examined the pharmacokinetic-pharmacodynamic relationships of these antibacterials in an in vitro glass hollow-fiber system that exposes parasites to dynamically changing drug concentrations. The same total dose and area under the concentration-time curve (AUC) of the drug was deployed either as a single short-lived high peak (bolus) or as a constant low concentration (infusion). All four antibacterials were unambiguously time-driven against malaria parasites: infusions had twice the efficacy of bolus regimens, for the same AUC. The time-dependent efficacy of ciprofloxacin against malaria is in contrast to its concentration-driven action against bacteria. In silico simulations of clinical dosing regimens and resulting pharmacokinetics revealed that current regimens do not maximize time above the MICs of these drugs. Our findings suggest that simple and rational changes to dosing may improve the efficacy of antibacterials against falciparum malaria.

AB - Antibacterial drugs are an important component of malaria therapy. We studied the interactions of clindamycin, tetracycline, chloramphenicol, and ciprofloxacin against Plasmodium falciparum under static and dynamic conditions. In microtiter plate assays (static conditions), and as expected, parasites displayed the delayed death response characteristic for apicoplast-targeting drugs. However, rescue by isopentenyl pyrophosphate was variable, ranging from 2,700-fold for clindamycin to just 1.7-fold for ciprofloxacin, suggesting that ciprofloxacin has targets other than the apicoplast. We also examined the pharmacokinetic-pharmacodynamic relationships of these antibacterials in an in vitro glass hollow-fiber system that exposes parasites to dynamically changing drug concentrations. The same total dose and area under the concentration-time curve (AUC) of the drug was deployed either as a single short-lived high peak (bolus) or as a constant low concentration (infusion). All four antibacterials were unambiguously time-driven against malaria parasites: infusions had twice the efficacy of bolus regimens, for the same AUC. The time-dependent efficacy of ciprofloxacin against malaria is in contrast to its concentration-driven action against bacteria. In silico simulations of clinical dosing regimens and resulting pharmacokinetics revealed that current regimens do not maximize time above the MICs of these drugs. Our findings suggest that simple and rational changes to dosing may improve the efficacy of antibacterials against falciparum malaria.

KW - Chemotherapy

KW - Chloramphenicol

KW - Ciprofloxacin

KW - Clindamycin

KW - Doxycycline

KW - Malaria

KW - Pharmacodynamics

KW - Pharmacokinetics

KW - PK/PD

KW - Plasmodium falciparum

KW - Tetracycline

UR - http://www.scopus.com/inward/record.url?scp=85073764432&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85073764432&partnerID=8YFLogxK

U2 - 10.1128/AAC.00416-19

DO - 10.1128/AAC.00416-19

M3 - Article

C2 - 31451506

AN - SCOPUS:85073764432

VL - 63

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 11

M1 - e00416-19

ER -