Target attainment of benzylpenicillin in patients with infective endocarditis

Magnus Bock; Johan G.C. Van Hasselt; Kurt Fuursted; Nikolaj Ihlemann; Sabine Gill; Ulrik Christiansen; Niels Eske Bruun; Hanne Elming; Jonas A. Povlsen; Lars Køber; Dan E. Høfsten; Emil L. Fosbøl; Mia M. Pries-Heje; Jens Jørgen Christensen; Flemming S. Rosenvinge; Christian Torp Pedersen; Jannik Helweg-Larsen; Niels Tønder; Kasper Iversen; Henning Bundgaard; Claus Moser

doi:10.1016/j.cmi.2025.04.025

Target attainment of benzylpenicillin in patients with infective endocarditis

Magnus Bock^*, Johan G.C. Van Hasselt, Kurt Fuursted, Nikolaj Ihlemann, Sabine Gill, Ulrik Christiansen, Niels Eske Bruun, Hanne Elming, Jonas A. Povlsen, Lars Køber, Dan E. Høfsten, Emil L. Fosbøl, Mia M. Pries-Heje, Jens Jørgen Christensen, Flemming S. Rosenvinge, Christian Torp Pedersen, Jannik Helweg-Larsen, Niels Tønder, Kasper Iversen, Henning BundgaardClaus Moser

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

Abstract

Objectives: Benzylpenicillin is commonly used to treat infective endocarditis, particularly for streptococcal infections. This study aimed to perform pharmacokinetic/pharmacodynamic analyses of benzylpenicillin to assess the probability of target attainment (PTA) across different pathogens, MIC values, pharmacokinetic/pharmacodynamic targets, and renal function levels. Methods: In the Partial Oral Endocarditis Treatment trial, patients with left-sided infective endocarditis were randomly assigned to either conventional intravenous or partial oral antibiotic treatment. This substudy included patients receiving intravenous benzylpenicillin (3000 mg q6h). Pharmacokinetic measurements were conducted, and a population pharmacokinetic model was developed to estimate PTAs through model-based simulations. Pharmacokinetic/pharmacodynamic targets were based on time above MIC (or 4 × MIC) of the free concentration (fT > MIC or fT > 4 × MIC). Results: A total of 75 patients were included, and 291 plasma concentrations were obtained. MIC values were available for 68 patients. Individual target attainment for 50% fT > MIC and 50% fT > 4 × MIC targets was 100% (56/56) and 94.6% (53/56) for streptococci, 100% (3/3) for staphylococci, but only 66.7% (6/9) and 33.3% (3/9) for Enterococcus faecalis. For more stringent targets of 100% fT > MIC and 100% fT > 4 × MIC, individual target attainment was 89.3% (50/56) and 75.0% (42/56) for streptococci, 100.0% (3/3) and 66.7% (2/3) for staphylococci, but 33.3% (3/9) and 11.1% (1/9) for E. faecalis. Simulations showed PTAs above 90% for MIC values ≤ 0.5 mg/L at the 50% fT > MIC target, and for MIC values ≤ 0.063 mg/L at 50% fT > 4 × MIC or 100% fT > MIC targets. Higher renal clearance was associated with substantially lower PTAs. Discussion: Intravenous benzylpenicillin achieved target levels in most patients with infective endocarditis, particularly for those infected with streptococci or susceptible staphylococci. However, low individual target attainment in patients with E. faecalis suggests limitations in treating enterococcal endocarditis, especially in patients with preserved renal function.

Original language	English
Journal	Clinical Microbiology and Infection
ISSN	1198-743X
DOIs	https://doi.org/10.1016/j.cmi.2025.04.025
Publication status	E-pub ahead of print - 2025

Bibliographical note

Publisher Copyright:
© 2025 European Society of Clinical Microbiology and Infectious Diseases

Keywords

Benzylpenicillin
Infective endocarditis
Pharmacodynamics
Pharmacokinetics
Target attainment

Access to Document

10.1016/j.cmi.2025.04.025Licence: CC BY

Cite this

Bock, M., Van Hasselt, J. G. C., Fuursted, K., Ihlemann, N., Gill, S., Christiansen, U., Bruun, N. E., Elming, H., Povlsen, J. A., Køber, L., Høfsten, D. E., Fosbøl, E. L., Pries-Heje, M. M., Christensen, J. J., Rosenvinge, F. S., Pedersen, C. T., Helweg-Larsen, J., Tønder, N., Iversen, K., ... Moser, C. (2025). Target attainment of benzylpenicillin in patients with infective endocarditis. Clinical Microbiology and Infection. Advance online publication. https://doi.org/10.1016/j.cmi.2025.04.025

Bock, M, Van Hasselt, JGC, Fuursted, K, Ihlemann, N, Gill, S, Christiansen, U, Bruun, NE, Elming, H, Povlsen, JA, Køber, L , Høfsten, DE , Fosbøl, EL, Pries-Heje, MM, Christensen, JJ, Rosenvinge, FS, Pedersen, CT, Helweg-Larsen, J, Tønder, N, Iversen, K , Bundgaard, H & Moser, C 2025, 'Target attainment of benzylpenicillin in patients with infective endocarditis', Clinical Microbiology and Infection. https://doi.org/10.1016/j.cmi.2025.04.025

@article{271cc12988cc4275b17e90e9d28ebeb1,

title = "Target attainment of benzylpenicillin in patients with infective endocarditis",

abstract = "Objectives: Benzylpenicillin is commonly used to treat infective endocarditis, particularly for streptococcal infections. This study aimed to perform pharmacokinetic/pharmacodynamic analyses of benzylpenicillin to assess the probability of target attainment (PTA) across different pathogens, MIC values, pharmacokinetic/pharmacodynamic targets, and renal function levels. Methods: In the Partial Oral Endocarditis Treatment trial, patients with left-sided infective endocarditis were randomly assigned to either conventional intravenous or partial oral antibiotic treatment. This substudy included patients receiving intravenous benzylpenicillin (3000 mg q6h). Pharmacokinetic measurements were conducted, and a population pharmacokinetic model was developed to estimate PTAs through model-based simulations. Pharmacokinetic/pharmacodynamic targets were based on time above MIC (or 4 × MIC) of the free concentration (fT > MIC or fT > 4 × MIC). Results: A total of 75 patients were included, and 291 plasma concentrations were obtained. MIC values were available for 68 patients. Individual target attainment for 50% fT > MIC and 50% fT > 4 × MIC targets was 100% (56/56) and 94.6% (53/56) for streptococci, 100% (3/3) for staphylococci, but only 66.7% (6/9) and 33.3% (3/9) for Enterococcus faecalis. For more stringent targets of 100% fT > MIC and 100% fT > 4 × MIC, individual target attainment was 89.3% (50/56) and 75.0% (42/56) for streptococci, 100.0% (3/3) and 66.7% (2/3) for staphylococci, but 33.3% (3/9) and 11.1% (1/9) for E. faecalis. Simulations showed PTAs above 90% for MIC values ≤ 0.5 mg/L at the 50% fT > MIC target, and for MIC values ≤ 0.063 mg/L at 50% fT > 4 × MIC or 100% fT > MIC targets. Higher renal clearance was associated with substantially lower PTAs. Discussion: Intravenous benzylpenicillin achieved target levels in most patients with infective endocarditis, particularly for those infected with streptococci or susceptible staphylococci. However, low individual target attainment in patients with E. faecalis suggests limitations in treating enterococcal endocarditis, especially in patients with preserved renal function.",

keywords = "Benzylpenicillin, Infective endocarditis, Pharmacodynamics, Pharmacokinetics, Target attainment",

author = "Magnus Bock and {Van Hasselt}, {Johan G.C.} and Kurt Fuursted and Nikolaj Ihlemann and Sabine Gill and Ulrik Christiansen and Bruun, {Niels Eske} and Hanne Elming and Povlsen, {Jonas A.} and Lars K{\o}ber and H{\o}fsten, {Dan E.} and Fosb{\o}l, {Emil L.} and Pries-Heje, {Mia M.} and Christensen, {Jens J{\o}rgen} and Rosenvinge, {Flemming S.} and Pedersen, {Christian Torp} and Jannik Helweg-Larsen and Niels T{\o}nder and Kasper Iversen and Henning Bundgaard and Claus Moser",

note = "Publisher Copyright: {\textcopyright} 2025 European Society of Clinical Microbiology and Infectious Diseases",

year = "2025",

doi = "10.1016/j.cmi.2025.04.025",

language = "English",

journal = "Clinical Microbiology and Infection",

issn = "1198-743X",

publisher = "Elsevier",

}

TY - JOUR

T1 - Target attainment of benzylpenicillin in patients with infective endocarditis

AU - Bock, Magnus

AU - Van Hasselt, Johan G.C.

AU - Fuursted, Kurt

AU - Ihlemann, Nikolaj

AU - Gill, Sabine

AU - Christiansen, Ulrik

AU - Bruun, Niels Eske

AU - Elming, Hanne

AU - Povlsen, Jonas A.

AU - Køber, Lars

AU - Høfsten, Dan E.

AU - Fosbøl, Emil L.

AU - Pries-Heje, Mia M.

AU - Christensen, Jens Jørgen

AU - Rosenvinge, Flemming S.

AU - Pedersen, Christian Torp

AU - Helweg-Larsen, Jannik

AU - Tønder, Niels

AU - Iversen, Kasper

AU - Bundgaard, Henning

AU - Moser, Claus

PY - 2025

Y1 - 2025

N2 - Objectives: Benzylpenicillin is commonly used to treat infective endocarditis, particularly for streptococcal infections. This study aimed to perform pharmacokinetic/pharmacodynamic analyses of benzylpenicillin to assess the probability of target attainment (PTA) across different pathogens, MIC values, pharmacokinetic/pharmacodynamic targets, and renal function levels. Methods: In the Partial Oral Endocarditis Treatment trial, patients with left-sided infective endocarditis were randomly assigned to either conventional intravenous or partial oral antibiotic treatment. This substudy included patients receiving intravenous benzylpenicillin (3000 mg q6h). Pharmacokinetic measurements were conducted, and a population pharmacokinetic model was developed to estimate PTAs through model-based simulations. Pharmacokinetic/pharmacodynamic targets were based on time above MIC (or 4 × MIC) of the free concentration (fT > MIC or fT > 4 × MIC). Results: A total of 75 patients were included, and 291 plasma concentrations were obtained. MIC values were available for 68 patients. Individual target attainment for 50% fT > MIC and 50% fT > 4 × MIC targets was 100% (56/56) and 94.6% (53/56) for streptococci, 100% (3/3) for staphylococci, but only 66.7% (6/9) and 33.3% (3/9) for Enterococcus faecalis. For more stringent targets of 100% fT > MIC and 100% fT > 4 × MIC, individual target attainment was 89.3% (50/56) and 75.0% (42/56) for streptococci, 100.0% (3/3) and 66.7% (2/3) for staphylococci, but 33.3% (3/9) and 11.1% (1/9) for E. faecalis. Simulations showed PTAs above 90% for MIC values ≤ 0.5 mg/L at the 50% fT > MIC target, and for MIC values ≤ 0.063 mg/L at 50% fT > 4 × MIC or 100% fT > MIC targets. Higher renal clearance was associated with substantially lower PTAs. Discussion: Intravenous benzylpenicillin achieved target levels in most patients with infective endocarditis, particularly for those infected with streptococci or susceptible staphylococci. However, low individual target attainment in patients with E. faecalis suggests limitations in treating enterococcal endocarditis, especially in patients with preserved renal function.

AB - Objectives: Benzylpenicillin is commonly used to treat infective endocarditis, particularly for streptococcal infections. This study aimed to perform pharmacokinetic/pharmacodynamic analyses of benzylpenicillin to assess the probability of target attainment (PTA) across different pathogens, MIC values, pharmacokinetic/pharmacodynamic targets, and renal function levels. Methods: In the Partial Oral Endocarditis Treatment trial, patients with left-sided infective endocarditis were randomly assigned to either conventional intravenous or partial oral antibiotic treatment. This substudy included patients receiving intravenous benzylpenicillin (3000 mg q6h). Pharmacokinetic measurements were conducted, and a population pharmacokinetic model was developed to estimate PTAs through model-based simulations. Pharmacokinetic/pharmacodynamic targets were based on time above MIC (or 4 × MIC) of the free concentration (fT > MIC or fT > 4 × MIC). Results: A total of 75 patients were included, and 291 plasma concentrations were obtained. MIC values were available for 68 patients. Individual target attainment for 50% fT > MIC and 50% fT > 4 × MIC targets was 100% (56/56) and 94.6% (53/56) for streptococci, 100% (3/3) for staphylococci, but only 66.7% (6/9) and 33.3% (3/9) for Enterococcus faecalis. For more stringent targets of 100% fT > MIC and 100% fT > 4 × MIC, individual target attainment was 89.3% (50/56) and 75.0% (42/56) for streptococci, 100.0% (3/3) and 66.7% (2/3) for staphylococci, but 33.3% (3/9) and 11.1% (1/9) for E. faecalis. Simulations showed PTAs above 90% for MIC values ≤ 0.5 mg/L at the 50% fT > MIC target, and for MIC values ≤ 0.063 mg/L at 50% fT > 4 × MIC or 100% fT > MIC targets. Higher renal clearance was associated with substantially lower PTAs. Discussion: Intravenous benzylpenicillin achieved target levels in most patients with infective endocarditis, particularly for those infected with streptococci or susceptible staphylococci. However, low individual target attainment in patients with E. faecalis suggests limitations in treating enterococcal endocarditis, especially in patients with preserved renal function.

KW - Benzylpenicillin

KW - Infective endocarditis

KW - Pharmacodynamics

KW - Pharmacokinetics

KW - Target attainment

U2 - 10.1016/j.cmi.2025.04.025

DO - 10.1016/j.cmi.2025.04.025

M3 - Journal article

C2 - 40306489

AN - SCOPUS:105005339932

SN - 1198-743X

JO - Clinical Microbiology and Infection

JF - Clinical Microbiology and Infection

ER -