Low minimal inhibitory concentrations of linezolid against multidrug-resistant tuberculosis strains

Weiss, Timo; Schönfeld, Nicolas; Otto-Knapp, Ralf; Bös, Lena; Bettermann, Gudrun; Mauch, H.; Bauer, Torsten T.; Rüssmann, Holger

doi:10.1183/09031936.00084614

Cited by 11 publications

(7 citation statements)

References 11 publications

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“…The target attainment probability, which is how well a dose of 150 mg, 300 mg, 600 mg, or 1,200 mg would achieve the EC 80 in the lung of tuberculosis patients at each MIC, was then calculated. We utilized three different MIC distributions from Spain, China, and Germany (466 clinical isolates) (41–43). The cumulative fraction of response (CFR) for each dose was then summated over the MIC distribution.…”

Section: Methodsmentioning

confidence: 99%

Linezolid Dose That Maximizes Sterilizing Effect While Minimizing Toxicity and Resistance Emergence for Tuberculosis

Srivastava

Magombedze

Koeuth

et al. 2017

Antimicrob Agents Chemother

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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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Section: Methodsmentioning

confidence: 99%

Linezolid Dose That Maximizes Sterilizing Effect While Minimizing Toxicity and Resistance Emergence for Tuberculosis

Srivastava

Magombedze

Koeuth

et al. 2017

Antimicrob Agents Chemother

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“…The literature review identified 738 studies, of which 18 studies were included in the analysis (Supporting Information S16). [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] At least one study was included from every region of the world. Summarizing the isolates from all included studies, a total of 2618 isolates could be included in the CFR determination.…”

Section: Clinical Trial Simulationsmentioning

confidence: 99%

Population pharmacokinetics and target attainment analysis of linezolid in multidrug‐resistant tuberculosis patients

Tietjen

Kroemer

Cattaneo

et al. 2021

Brit J Clinical Pharma

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This study investigates the pharmacokinetic/pharmacodynamic (PK/PD) target attainment of linezolid in patients infected with multidrug-resistant (MDR) tuberculosis (TB).Methods: A pharmacometric model was developed including 244 timed linezolid concentration samples from 39 patients employing NONMEM 7.4. The probability of target attainment (PTA, PK/PD target: unbound (f) area-under-the-concentrationtime-curve (AUC)/minimal inhibitory concentration (MIC) of 119) as well as a regionspecific cumulative fraction of response (CFR) were estimated for different dosing regimens.Results: A one-compartment model with linear elimination with a clearance (CL) of 7.69 L/h (interindividual variability 34.1%), a volume of distribution (Vd) of 45.2 L and an absorption constant (KA) of 0.679 h À1 (interoccasion variability 143.7%) allometric scaled by weight best described the PK of linezolid. The PTA at an MIC of 0.5 mg/L was 55% or 97% if patients receiving 300 or 600 mg twice daily, respectively. CFRs varied greatly among populations and geographic regions. A desirable global CFR of ≥90% was achieved if linezolid was administered at a dose of 600 mg twice daily but not at a dose of 300 mg twice daily. Conclusion:This study showed that a dose of 300 mg twice daily of linezolid might not be sufficient to treat MDR-TB patients from a PK/PD perspective. Thus, it might be recommendable to start with a higher dose of 600 mg twice daily to ensure PK/PD target attainment. Hereby, therapeutic drug monitoring and MIC determination should be performed to control PK/PD target attainment as linezolid shows high variability in its PK in the TB population.

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“…LZD has been shown to have similar minimal inhibitory concentrations (MICs) for MDR-TB strains as for non-MDR strains [10]. In addition, LZD has been reported to have a similar in vitro bactericidal effect on latent Mycobacterium tuberculosis bacilli as rifampicin [11].…”

Section: Introductionmentioning

confidence: 99%

Simple strategy to assess linezolid exposure in patients with multi-drug-resistant and extensively-drug-resistant tuberculosis

Kamp

Bolhuis

Tiberi

et al. 2017

International Journal of Antimicrobial Agents

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Low minimal inhibitory concentrations of linezolid against multidrug-resistant tuberculosis strains

Cited by 11 publications

References 11 publications

Linezolid Dose That Maximizes Sterilizing Effect While Minimizing Toxicity and Resistance Emergence for Tuberculosis

Linezolid Dose That Maximizes Sterilizing Effect While Minimizing Toxicity and Resistance Emergence for Tuberculosis

Population pharmacokinetics and target attainment analysis of linezolid in multidrug‐resistant tuberculosis patients

Simple strategy to assess linezolid exposure in patients with multi-drug-resistant and extensively-drug-resistant tuberculosis

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