LInezolid Monitoring to MInimise Toxicity (LIMMIT1): A multicentre retrospective review of patients receiving linezolid therapy and the impact of therapeutic drug monitoring

Lau, Cindy; Marriott, Deborah; Bui, Jessica; FIGTREE, Melanie; GOULD, Michael; Chubaty, Adriana J; Su, Yuen; Adhikari, Suman; KONECNY, Pam; KOZIEROWSKI, Kristi; HOLLAND, Taylor; MILLIKEN, Eliza; AKRAM, Ayesha; MCNAMARA, Alexander; SUN, Yihui; Hal, Sebastiaan J. van; Patanwala, Asad E.; Shahabi-Sirjani, Aryan; GRAY, Timothy; YEO, Chin Yen; NETLUCH, Angela; HALENA, Stephanie; APPAY, Marcelle; ALAMEDDINE, Rozanna; YIN, Fiona; NGUYEN, Quoc; SO, Mei-Yi; Sandaradura, Indy; KIM, Hannah Yejin; GALIMAM, Semun; CERRUTO, Nicole; Lai, Tony; GILBEY, Timothy; Daveson, Kathryn; Reuter, Stephanie E; Penm, Jonathan; Alffenaar, Jan-Willem

doi:10.1016/j.ijantimicag.2023.106783

Cited by 13 publications

(12 citation statements)

References 30 publications

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“…Recent studies have found that polymorphisms in CYP3A5 may influence LZD and BDQ clearance. The CYP3A5 *1 haplotype was associated with a nearly six-fold risk of LZD underexposure compared with *3/*3, and the *3 haplotype was associated with slower clearance of BDQ, including 30% lower clearance for homozygous individuals (*3/*3) 26,27,28 . While we analytically validated our assay to correctly identify these polymorphisms, our clinical cohort did not include individuals receiving these drugs, and further studies are needed to confirm the importance of these variants in diverse populations.…”

Section: Discussionmentioning

confidence: 99%

“…We searched published literature for pharmacogenetic markers of metabolism for drugs that are recommended by the World Health Organization for treatment of TB, including multidrugresistant or RIF-resistant TB (MDR/RR-TB). We selected 15 well characterized single nucleotide polymorphisms (SNP) for which high quality studies had demonstrated associations with pharmacokinetic parameters, adverse events, or treatment outcomes [18][19][20][21][22][23][24][25][26][27][28] . The 15 SNPs, which had pharmacogenomic associations with INH, RIF, LZD or BDQ, occurred in five genes: N-acetyltransferase 2 (NAT2), cytochrome P450 family 2 subfamily E member 1 (CYP2E1), solute carrier organic anion transporter family member 1B1 (SLCO1B1), arylacetamide deacetylase (AADAC) and cytochrome P450 family 3 subfamily A member 5 (CYP3A5) 31 .…”

Section: Selection Of Pharmacogenomic Markersmentioning

confidence: 99%

“…A study in South Africa found that patients with mutation in the SLCO1B1 gene decreased RIF AUC. 25 Mutations in cytochrome P450 gene CYP3A5 are associated with faster LZD clearance, putting patients at higher risk of underexposure when treated at standard dose 26,27 . In another study on South Africans treated for drug-resistant TB, CYP3A5*3 haplotype was associated with slower BDQ clearance 28. Modification of anti-TB drug doses based on pharmacogenomic data can improve PK target attainment, reduce toxicity risk, and improve treatment outcomes.…”

Section: Introductionmentioning

confidence: 99%

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A Nanopore sequencing-based pharmacogenomic panel to personalize tuberculosis drug dosing

Verma,

Esther da Silva,

Rockwood

et al. 2023

Preprint

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RationaleStandardized dosing of anti-tubercular (TB) drugs leads to variable plasma drug levels, which are associated with adverse drug reactions, delayed treatment response, and relapse. Mutations in genes affecting drug metabolism explain considerable interindividual pharmacokinetic variability; however, pharmacogenomic (PGx) assays that predict metabolism of anti-TB drugs have been lacking.ObjectivesTo develop a Nanopore sequencing panel and validate its performance in active TB patients to personalize treatment dosing.Measurements and Main ResultsWe developed a Nanopore sequencing panel targeting 15 single nucleotide polymorphisms (SNP) in 5 genes affecting the metabolism of isoniazid (INH), rifampin (RIF), linezolid and bedaquiline. For validation, we sequenced DNA samples (n=48) from the 1000 genomes project and compared variant calling accuracy with Illumina genome sequencing. We then sequenced DNA samples from patients with active TB (n=100) from South Africa on a MinION Mk1C and evaluated the relationship between genotypes and pharmacokinetic parameters for INH and RIF.ResultsThe PGx panel achieved 100% concordance with Illumina sequencing in variant identification for the samples from the 1000 Genomes Project. In the clinical cohort, coverage was >100x for 1498/1500 (99.8%) amplicons across the 100 samples. One third (33%) of participants were identified as slow, 47% were intermediate and 20% were rapid isoniazid acetylators. Isoniazid clearance was significantly impacted by acetylator status (p<0.0001) with median (IQR) clearances of 11.2 L/h (9.3-13.4), 27.2 L/h (22.0-31.7), and 45.1 L/h (34.1-51.1) in slow, intermediate, and rapid acetylators. Rifampin clearance was 17.3% (2.50-29.9) lower in individuals with homozygousAADACrs1803155 G>A substitutions (p=0.0015).ConclusionTargeted sequencing can enable detection of polymorphisms influencing TB drug metabolism on a low-cost, portable instrument to personalize dosing for TB treatment or prevention.SummaryThis manuscript describes the development and validation of Nanopore sequencing panel to detect host pharmacogenomic markers to guide personalized drug dosing for treatment or prevention of tuberculosis.This article has an online data supplement, which is accessible from this issue’s table of content online atwww.atsjournals.org

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Section: Discussionmentioning

confidence: 99%

Section: Selection Of Pharmacogenomic Markersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Nanopore sequencing-based pharmacogenomic panel to personalize tuberculosis drug dosing

Verma,

Esther da Silva,

Rockwood

et al. 2023

Preprint

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“…If available, use TDM, aiming for a trough concentration of 2–7 mg/l after 48 h of therapy, to ensure efficacy and minimize toxicity. Use of linezolid TDM significantly reduced the risk of myelosuppression associated with prolonged treatment duration (>14 days) [90 ▪▪ ]. Other toxicities, including optic neuropathy, peripheral neuropathy, lactic acidosis and serotonin toxicity can occur [92].…”

Section: Linezolidmentioning

confidence: 99%

“…Thrombocytopenia has been reported when linezolid trough concentrations exceed 7–10 mg/l or a 24-h AUC of 300–350 mg∗h/l, especially when used for prolonged periods (e.g. 21 days) [89,90 ▪▪ ,91]. If available, use TDM, aiming for a trough concentration of 2–7 mg/l after 48 h of therapy, to ensure efficacy and minimize toxicity.…”

Section: Linezolidmentioning

confidence: 99%

Optimal drug therapy for Staphylococcus aureus bacteraemia in adults

Legg,

Davis,

Roberts

2023

Current Opinion in Critical Care

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Purpose of review Staphylococcus aureus is a significant human pathogen, causing a variety of infections, from skin and soft tissue infections to endocarditis, bone and joint infections and deep tissue abscesses. Mortality from S. aureus bacteraemia remains high, without major therapeutic advances in recent decades. Recent findings In recent years, optimized dosing of antibiotics is increasingly being recognized as a cornerstone of management for severe infections including S. aureus bacteraemia. This comprehensive review details the pharmacokinetics/pharmacodynamics (PK/PD) targets for commonly used antistaphylococcal antibiotics and the doses predicted to achieve them in clinical practice. Recent advances in dosing of teicoplanin and use of cefazolin in CNS infections and findings from combination therapy studies are discussed. Drug exposure relationships related to toxicity are also detailed. Summary This review details the different PK/PD targets for drugs used to treat S. aureus bacteraemia and how to apply them in various scenarios. The drug doses that achieve them, and the risks of toxicity are also provided.

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Evaluation of pharmacokinetic target attainment and hematological toxicity of linezolid in pediatric patients

Abouelkheir,

Aldawsari,

Ghonem

et al. 2024

Eur J Clin Pharmacol

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LInezolid Monitoring to MInimise Toxicity (LIMMIT1): A multicentre retrospective review of patients receiving linezolid therapy and the impact of therapeutic drug monitoring

Cited by 13 publications

References 30 publications

A Nanopore sequencing-based pharmacogenomic panel to personalize tuberculosis drug dosing

A Nanopore sequencing-based pharmacogenomic panel to personalize tuberculosis drug dosing

Optimal drug therapy for Staphylococcus aureus bacteraemia in adults

Evaluation of pharmacokinetic target attainment and hematological toxicity of linezolid in pediatric patients

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