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 af dette arbejde

Publikation: Bidrag til tidsskrift › Artikel › Forskning › 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.

Originalsprog	Engelsk
Sider (fra-til)	1350-1355
Antal sider	6
Tidsskrift	Clinical Microbiology and Infection
Vol/bind	31
Udgave nummer	8
Tidlig onlinedato	28 apr. 2025
DOI	https://doi.org/10.1016/j.cmi.2025.04.025
Status	Udgivet - aug. 2025

Finansiering

Bevillingsgivere	Bevillingsgivernummer
Hjerteforeningen
Region Hovedstaden
Brødrene Hartmanns Fond
Borgmester Svend Åge Andersens Fond
Novo Nordisk Foundation	NNF17OC0025074

Adgang til dokumentet

10.1016/j.cmi.2025.04.025

Citationsformater

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, 31(8), 1350-1355. https://doi.org/10.1016/j.cmi.2025.04.025

@article{3a93e643b7404f3d9434f6552dfcb66d,

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 = "Administration, Intravenous, Administration, Oral, Adult, Aged, Anti-Bacterial Agents/pharmacokinetics, Endocarditis, Bacterial/drug therapy, Endocarditis/drug therapy, Female, Humans, Male, Microbial Sensitivity Tests, Middle Aged, Penicillin G/pharmacokinetics, Streptococcal Infections/drug therapy, Streptococcus/drug effects, Pharmacodynamics, Benzylpenicillin, Target attainment, Infective endocarditis, Pharmacokinetics",

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",

year = "2025",

month = aug,

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

language = "English",

volume = "31",

pages = "1350--1355",

journal = "Clinical Microbiology and Infection",

issn = "1198-743X",

publisher = "Elsevier B.V.",

number = "8",

}

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, bind 31, nr. 8, s. 1350-1355. https://doi.org/10.1016/j.cmi.2025.04.025

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 - 2025/8

Y1 - 2025/8

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 - Administration, Intravenous

KW - Administration, Oral

KW - Adult

KW - Aged

KW - Anti-Bacterial Agents/pharmacokinetics

KW - Endocarditis, Bacterial/drug therapy

KW - Endocarditis/drug therapy

KW - Female

KW - Humans

KW - Male

KW - Microbial Sensitivity Tests

KW - Middle Aged

KW - Penicillin G/pharmacokinetics

KW - Streptococcal Infections/drug therapy

KW - Streptococcus/drug effects

KW - Pharmacodynamics

KW - Benzylpenicillin

KW - Target attainment

KW - Infective endocarditis

KW - Pharmacokinetics

U2 - 10.1016/j.cmi.2025.04.025

DO - 10.1016/j.cmi.2025.04.025

M3 - Article

C2 - 40306489

SN - 1198-743X

VL - 31

SP - 1350

EP - 1355

JO - Clinical Microbiology and Infection

JF - Clinical Microbiology and Infection

IS - 8

ER -

Target Attainment of Benzylpenicillin in Patients with Infective Endocarditis

Abstract

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