High rifampicin peak plasma concentrations accelerate the slow phase of bacterial decline in tuberculosis patients: Evidence for heteroresistance

Antibiotic treatments are often associated with a late slowdown in bacterial killing. This separates the killing of bacteria into at least two distinct phases: a quick phase followed by a slower phase, the latter of which is linked to treatment success. Current mechanistic explanations for the in vi...

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Vydané v:PLoS computational biology Ročník 19; číslo 4; s. e1011000
Hlavní autori: Martinecz, Antal, Boeree, Martin J., Diacon, Andreas H., Dawson, Rodney, Hemez, Colin, Aarnoutse, Rob E., Abel zur Wiesch, Pia
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States Public Library of Science 01.04.2023
Public Library of Science (PLoS)
Predmet:
Analysis
Anti-Bacterial Agents - pharmacology
Antibiotics
Bacteria
Biology and Life Sciences
Care and treatment
Clinical trials
Coexistence
Datasets
Dosage and administration
Drug dosages
Estimates
Humans
Mathematical models
Medicine and Health Sciences
Mortality
Mycobacterium tuberculosis
Patients
Pharmacodynamics
Pharmacokinetics
Research and Analysis Methods
Rifampin
Rifampin - pharmacokinetics
Rifampin - therapeutic use
Sputum
Statistical analysis
Success
Tuberculosis
Tuberculosis - drug therapy
United States
ISSN:1553-7358, 1553-734X, 1553-7358
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Popis
Shrnutí:Antibiotic treatments are often associated with a late slowdown in bacterial killing. This separates the killing of bacteria into at least two distinct phases: a quick phase followed by a slower phase, the latter of which is linked to treatment success. Current mechanistic explanations for the in vitro slowdown are either antibiotic persistence or heteroresistance. Persistence is defined as the switching back and forth between susceptible and non-susceptible states, while heteroresistance is defined as the coexistence of bacteria with heterogeneous susceptibilities. Both are also thought to cause a slowdown in the decline of bacterial populations in patients and therefore complicate and prolong antibiotic treatments. Reduced bacterial death rates over time are also observed within tuberculosis patients, yet the mechanistic reasons for this are unknown and therefore the strategies to mitigate them are also unknown. We analyse a dose ranging trial for rifampicin in tuberculosis patients and show that there is a slowdown in the decline of bacteria. We show that the late phase of bacterial killing depends more on the peak drug concentrations than the total drug exposure. We compare these to pharmacokinetic-pharmacodynamic models of rifampicin heteroresistance and persistence. We find that the observation on the slow phase's dependence on pharmacokinetic measures, specifically peak concentrations are only compatible with models of heteroresistance and incompatible with models of persistence. The quantitative agreement between heteroresistance models and observations is very good ([Formula: see text]). To corroborate the importance of the slowdown, we validate our results by estimating the time to sputum culture conversion and compare the results to a different dose ranging trial. Our findings indicate that higher doses, specifically higher peak concentrations may be used to optimize rifampicin treatments by accelerating bacterial killing in the slow phase. It adds to the growing body of literature supporting higher rifampicin doses for shortening tuberculosis treatments.
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AM is currently an employee of AstraZeneca. However, the work was carried out before he was an employee of AstraZeneca. Therefore, no competing interests exist.
ISSN:1553-7358
1553-734X
1553-7358
DOI:10.1371/journal.pcbi.1011000