Population pharmacokinetics/pharmacodynamics of minocycline plus rifampicin in patients with complicated skin and skin structure infections caused by MRSA

Sonia Luque Pardos; William Hope; Antigone Kotsaki; Shampa Das; Evangelos J Giamarellos-Bourboulis; Theano Kontopoulouk; Karolina Akinosoglou; Miriam O'Hare; Marie L G Attwood; Karen E Bowker; Alan R Noel; Andrew M Lovering; Mark A J Bayliss; Rebecca N Evans; Alasdair P MacGowan

doi:10.1093/jac/dkae363

Population pharmacokinetics/pharmacodynamics of minocycline plus rifampicin in patients with complicated skin and skin structure infections caused by MRSA

Sonia Luque Pardos
, William Hope
, Antigone Kotsaki
, Shampa Das
, Evangelos J Giamarellos-Bourboulis
, Theano Kontopoulouk
, Karolina Akinosoglou
, Miriam O'Hare
, Marie L G Attwood
, Karen E Bowker
, Alan R Noel
, Andrew M Lovering
, Mark A J Bayliss
, Rebecca N Evans
, Alasdair P MacGowan^*

^*Corresponding author for this work

Bristol Medical School (PHS)

Research output: Contribution to journal › Article (Academic Journal) › peer-review

3 Citations (Scopus)

Abstract

BACKGROUND: The population pharmacokinetics/pharmacodynamics (PK/PD) of minocycline, rifampicin and linezolid in patients with complicated skin and soft tissue infections (cSSTIs) caused by MRSA are described.

METHODS: Samples were collected in a Phase 4 study of oral minocycline plus rifampicin versus linezolid showing minocycline plus rifampicin to be non-inferior to linezolid. Antibiotics were assayed by HPLC or LC-MS, and a population PK model was developed using Pmetrics. The association between PK/PD indices and patient outcomes was explored.

RESULTS: A three-compartment model (with an absorption compartment) with first-order input and elimination best described the data for the three drugs. No covariates were included in the final model. The population median values (95% credibility limits) of the clearance and volume of distribution were 7.412 L/h (5.121-8.361) and 14.155 L (6.799-33.901) for minocycline, 5.683 L/h (3.703-7.726) and 7.736 L (6.031-8.948) for rifampicin, and 1.970 L/h (1.326-2.499) and 20.169 L (12.857-32.629) for linezolid, respectively. Maximum a posteriori probability-Bayesian estimation plots of observed versus predicted had a slope of 0.999 r20.967 for minocycline, slope 0.998 r20.769 for rifampicin and slope 0.998 r20.895 for linezolid. PK/PD indices were not related to clinical outcome. Taking a translational minocycline fAUC24h/MIC target of >0.5 for minocycline in the presence of rifampicin, 96% (49/51) of patients reached the target.

CONCLUSIONS: Population PK models of minocycline, rifampicin and linezolid were developed in patients with MRSA cSSTI and almost all patients reached the predefined PD index targets. As a result, neither AUC, MIC nor the AUC/MIC ratio could be related to clinical outcome.

Original language	English
Pages (from-to)	3303-3312
Number of pages	10
Journal	The Journal of antimicrobial chemotherapy
Volume	79
Issue number	12
Early online date	16 Oct 2024
DOIs	https://doi.org/10.1093/jac/dkae363
Publication status	Published - 1 Dec 2024

Bibliographical note

© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact [email protected].

Keywords

Humans
Rifampin/pharmacokinetics
Minocycline/pharmacokinetics
Anti-Bacterial Agents/pharmacokinetics
Methicillin-Resistant Staphylococcus aureus/drug effects
Male
Linezolid/pharmacokinetics
Staphylococcal Skin Infections/drug therapy
Microbial Sensitivity Tests
Young Adult
Treatment Outcome
Soft Tissue Infections/drug therapy
Drug Therapy, Combination

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Pardos, S. L., Hope, W., Kotsaki, A., Das, S., Giamarellos-Bourboulis, E. J., Kontopoulouk, T., Akinosoglou, K., O'Hare, M., Attwood, M. L. G., Bowker, K. E., Noel, A. R., Lovering, A. M., Bayliss, M. A. J., Evans, R. N., & MacGowan, A. P. (2024). Population pharmacokinetics/pharmacodynamics of minocycline plus rifampicin in patients with complicated skin and skin structure infections caused by MRSA. The Journal of antimicrobial chemotherapy, 79(12), 3303-3312. https://doi.org/10.1093/jac/dkae363

@article{53e66d6d958249bd9159333a09c94f25,

title = "Population pharmacokinetics/pharmacodynamics of minocycline plus rifampicin in patients with complicated skin and skin structure infections caused by MRSA",

abstract = "BACKGROUND: The population pharmacokinetics/pharmacodynamics (PK/PD) of minocycline, rifampicin and linezolid in patients with complicated skin and soft tissue infections (cSSTIs) caused by MRSA are described.METHODS: Samples were collected in a Phase 4 study of oral minocycline plus rifampicin versus linezolid showing minocycline plus rifampicin to be non-inferior to linezolid. Antibiotics were assayed by HPLC or LC-MS, and a population PK model was developed using Pmetrics. The association between PK/PD indices and patient outcomes was explored.RESULTS: A three-compartment model (with an absorption compartment) with first-order input and elimination best described the data for the three drugs. No covariates were included in the final model. The population median values (95\% credibility limits) of the clearance and volume of distribution were 7.412 L/h (5.121-8.361) and 14.155 L (6.799-33.901) for minocycline, 5.683 L/h (3.703-7.726) and 7.736 L (6.031-8.948) for rifampicin, and 1.970 L/h (1.326-2.499) and 20.169 L (12.857-32.629) for linezolid, respectively. Maximum a posteriori probability-Bayesian estimation plots of observed versus predicted had a slope of 0.999 r20.967 for minocycline, slope 0.998 r20.769 for rifampicin and slope 0.998 r20.895 for linezolid. PK/PD indices were not related to clinical outcome. Taking a translational minocycline fAUC24h/MIC target of >0.5 for minocycline in the presence of rifampicin, 96\% (49/51) of patients reached the target.CONCLUSIONS: Population PK models of minocycline, rifampicin and linezolid were developed in patients with MRSA cSSTI and almost all patients reached the predefined PD index targets. As a result, neither AUC, MIC nor the AUC/MIC ratio could be related to clinical outcome.",

keywords = "Humans, Rifampin/pharmacokinetics, Minocycline/pharmacokinetics, Anti-Bacterial Agents/pharmacokinetics, Methicillin-Resistant Staphylococcus aureus/drug effects, Male, Linezolid/pharmacokinetics, Staphylococcal Skin Infections/drug therapy, Microbial Sensitivity Tests, Young Adult, Treatment Outcome, Soft Tissue Infections/drug therapy, Drug Therapy, Combination",

author = "Pardos, \{Sonia Luque\} and William Hope and Antigone Kotsaki and Shampa Das and Giamarellos-Bourboulis, \{Evangelos J\} and Theano Kontopoulouk and Karolina Akinosoglou and Miriam O'Hare and Attwood, \{Marie L G\} and Bowker, \{Karen E\} and Noel, \{Alan R\} and Lovering, \{Andrew M\} and Bayliss, \{Mark A J\} and Evans, \{Rebecca N\} and MacGowan, \{Alasdair P\}",

note = "{\textcopyright} The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact [email protected].",

year = "2024",

month = dec,

day = "1",

doi = "10.1093/jac/dkae363",

language = "English",

volume = "79",

pages = "3303--3312",

journal = "The Journal of antimicrobial chemotherapy",

issn = "0305-7453",

publisher = "Oxford University Press",

number = "12",

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Pardos, SL, Hope, W, Kotsaki, A, Das, S, Giamarellos-Bourboulis, EJ, Kontopoulouk, T, Akinosoglou, K, O'Hare, M, Attwood, MLG, Bowker, KE, Noel, AR, Lovering, AM, Bayliss, MAJ, Evans, RN & MacGowan, AP 2024, 'Population pharmacokinetics/pharmacodynamics of minocycline plus rifampicin in patients with complicated skin and skin structure infections caused by MRSA', The Journal of antimicrobial chemotherapy, vol. 79, no. 12, pp. 3303-3312. https://doi.org/10.1093/jac/dkae363

Population pharmacokinetics/pharmacodynamics of minocycline plus rifampicin in patients with complicated skin and skin structure infections caused by MRSA. / Pardos, Sonia Luque; Hope, William; Kotsaki, Antigone et al.
In: The Journal of antimicrobial chemotherapy, Vol. 79, No. 12, 01.12.2024, p. 3303-3312.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

TY - JOUR

T1 - Population pharmacokinetics/pharmacodynamics of minocycline plus rifampicin in patients with complicated skin and skin structure infections caused by MRSA

AU - Pardos, Sonia Luque

AU - Hope, William

AU - Kotsaki, Antigone

AU - Das, Shampa

AU - Giamarellos-Bourboulis, Evangelos J

AU - Kontopoulouk, Theano

AU - Akinosoglou, Karolina

AU - O'Hare, Miriam

AU - Attwood, Marie L G

AU - Bowker, Karen E

AU - Noel, Alan R

AU - Lovering, Andrew M

AU - Bayliss, Mark A J

AU - Evans, Rebecca N

AU - MacGowan, Alasdair P

N1 - © The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact [email protected].

PY - 2024/12/1

Y1 - 2024/12/1

N2 - BACKGROUND: The population pharmacokinetics/pharmacodynamics (PK/PD) of minocycline, rifampicin and linezolid in patients with complicated skin and soft tissue infections (cSSTIs) caused by MRSA are described.METHODS: Samples were collected in a Phase 4 study of oral minocycline plus rifampicin versus linezolid showing minocycline plus rifampicin to be non-inferior to linezolid. Antibiotics were assayed by HPLC or LC-MS, and a population PK model was developed using Pmetrics. The association between PK/PD indices and patient outcomes was explored.RESULTS: A three-compartment model (with an absorption compartment) with first-order input and elimination best described the data for the three drugs. No covariates were included in the final model. The population median values (95% credibility limits) of the clearance and volume of distribution were 7.412 L/h (5.121-8.361) and 14.155 L (6.799-33.901) for minocycline, 5.683 L/h (3.703-7.726) and 7.736 L (6.031-8.948) for rifampicin, and 1.970 L/h (1.326-2.499) and 20.169 L (12.857-32.629) for linezolid, respectively. Maximum a posteriori probability-Bayesian estimation plots of observed versus predicted had a slope of 0.999 r20.967 for minocycline, slope 0.998 r20.769 for rifampicin and slope 0.998 r20.895 for linezolid. PK/PD indices were not related to clinical outcome. Taking a translational minocycline fAUC24h/MIC target of >0.5 for minocycline in the presence of rifampicin, 96% (49/51) of patients reached the target.CONCLUSIONS: Population PK models of minocycline, rifampicin and linezolid were developed in patients with MRSA cSSTI and almost all patients reached the predefined PD index targets. As a result, neither AUC, MIC nor the AUC/MIC ratio could be related to clinical outcome.

AB - BACKGROUND: The population pharmacokinetics/pharmacodynamics (PK/PD) of minocycline, rifampicin and linezolid in patients with complicated skin and soft tissue infections (cSSTIs) caused by MRSA are described.METHODS: Samples were collected in a Phase 4 study of oral minocycline plus rifampicin versus linezolid showing minocycline plus rifampicin to be non-inferior to linezolid. Antibiotics were assayed by HPLC or LC-MS, and a population PK model was developed using Pmetrics. The association between PK/PD indices and patient outcomes was explored.RESULTS: A three-compartment model (with an absorption compartment) with first-order input and elimination best described the data for the three drugs. No covariates were included in the final model. The population median values (95% credibility limits) of the clearance and volume of distribution were 7.412 L/h (5.121-8.361) and 14.155 L (6.799-33.901) for minocycline, 5.683 L/h (3.703-7.726) and 7.736 L (6.031-8.948) for rifampicin, and 1.970 L/h (1.326-2.499) and 20.169 L (12.857-32.629) for linezolid, respectively. Maximum a posteriori probability-Bayesian estimation plots of observed versus predicted had a slope of 0.999 r20.967 for minocycline, slope 0.998 r20.769 for rifampicin and slope 0.998 r20.895 for linezolid. PK/PD indices were not related to clinical outcome. Taking a translational minocycline fAUC24h/MIC target of >0.5 for minocycline in the presence of rifampicin, 96% (49/51) of patients reached the target.CONCLUSIONS: Population PK models of minocycline, rifampicin and linezolid were developed in patients with MRSA cSSTI and almost all patients reached the predefined PD index targets. As a result, neither AUC, MIC nor the AUC/MIC ratio could be related to clinical outcome.

KW - Humans

KW - Rifampin/pharmacokinetics

KW - Minocycline/pharmacokinetics

KW - Anti-Bacterial Agents/pharmacokinetics

KW - Methicillin-Resistant Staphylococcus aureus/drug effects

KW - Male

KW - Linezolid/pharmacokinetics

KW - Staphylococcal Skin Infections/drug therapy

KW - Microbial Sensitivity Tests

KW - Young Adult

KW - Treatment Outcome

KW - Soft Tissue Infections/drug therapy

KW - Drug Therapy, Combination

U2 - 10.1093/jac/dkae363

DO - 10.1093/jac/dkae363

M3 - Article (Academic Journal)

C2 - 39412246

SN - 0305-7453

VL - 79

SP - 3303

EP - 3312

JO - The Journal of antimicrobial chemotherapy

JF - The Journal of antimicrobial chemotherapy

IS - 12

ER -

Population pharmacokinetics/pharmacodynamics of minocycline plus rifampicin in patients with complicated skin and skin structure infections caused by MRSA

Abstract

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Keywords

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