Population Pharmacokinetic Modeling and Probability of Target Attainment of Ceftaroline in Brain and Soft Tissues

Helfer, Victória Etges; Zavascki, Alexandre Prehn; Zeitlinger, Markus; Araújo, Bibiana Verlindo de; Costa, Teresa Dalla

doi:10.1128/aac.00741-22

Cited by 12 publications

(15 citation statements)

References 47 publications

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“…The PK parameter estimates were in the range of previous population PK analyses involving healthy volunteers (CL 10.9 L/h vs. 10.7 L/h for CL CR_median = 120 mL/min/1.73 m 2 and age median = 28 years [ 17 ], 11.9 L/h for CL CR_median = 145 mL/min [ 11 ]; V total 23.1 L vs. 19.0 L [ 17 ], 24.9 L for TBW median = 74.5 kg [ 11 ]). The interindividual variability associated with clearance was 15.6% and was in line with other studies including healthy volunteers (16.4% [ 11 ], 18.4% [ 30 ]). Potential sources of variability include renal excretion, factors influencing saturable elimination, or other covariates.…”

Section: Discussionsupporting

confidence: 91%

Impact of Key Components of Intensified Ceftaroline Dosing on Pharmacokinetic/Pharmacodynamic Target Attainment

Minichmayr,

Wicha,

Matzneller

et al. 2023

Clin Pharmacokinet

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Background and Objective Ceftaroline fosamil is a β-lactam antibiotic approved as a 600 mg twice daily dose (≤1 h infusion, ‘standard dosing’) or a 600 mg thrice daily dose (2 h infusion) to treat complicated skin and soft tissue infections caused by Staphylococcus aureus (minimum inhibitory concentration [MIC] 2–4 mg/L). We sought to systematically evaluate the relative impact of the three key components of the intensified dosing regimen (i.e. shortened dosing interval, prolonged infusion duration and increased total daily dose [TDD]) on the pharmacokinetic/pharmacodynamic (PK/PD) target attainment given different grades of bacterial susceptibility. Methods A population PK model was developed using data from 12 healthy volunteers (EudraCT-2012-005134-11) receiving standard or intensified dosing. PK/PD target attainment ( ƒ T >MIC = 35% and 100%) after 24 h was compared following systematically varied combinations of the (1) dosing interval (every 12 h [q12h]→ every 8 h [q8h]); (2) infusion duration (1 h→2 h); and (3) individual and total daily dose (400→900 mg, i.e. TDD 1200→1800 mg), as well as for varying susceptibility of S. aureus (MIC 0.032–8 mg/L). Results A two-compartment model with linear elimination adequately described ceftaroline concentrations ( n = 274). The relevance of the dosing components dosing interval/infusion duration/TDD for ƒ T >MIC systematically changed with pathogen susceptibility. For susceptible pathogens with MIC ≤1 mg/L, shortened dosing intervals appeared as the main driver of the improved target attainment associated with the intensified dosing regimen, followed by increased TDD and infusion duration. For less susceptible pathogens, the advantage of q8h dosing and 2 h infusions declined, and increased TDD improved ƒ T >MIC the most. Conclusion The analysis calls to mind consideration of dose increases when prolonging the infusion duration in the case of low bacterial susceptibility. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-023-01325-4.

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Section: Discussionsupporting

confidence: 91%

Impact of Key Components of Intensified Ceftaroline Dosing on Pharmacokinetic/Pharmacodynamic Target Attainment

Minichmayr,

Wicha,

Matzneller

et al. 2023

Clin Pharmacokinet

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“…Ceftaroline is one of the newer cephalosporins approved by the FDA and has a desirable extension of the beta-lactam spectrum of activity to include methicillin-resistant Staphylococcus aureus (MRSA). Ceftaroline has had limited evaluation for CNS infections but has been used off-label for this indication [ 70 ]. Similar to the other beta-lactams, it has low CNS penetration.…”

Section: Beta-lactam Antibioticsmentioning

confidence: 99%

“…Similar to the other beta-lactams, it has low CNS penetration. In a Monte Carlo simulation, Helfer et al found that ceftaroline had 90% predicted target attainment for fT > MIC of 28.8% with an MIC of 1 mg/L; this improved to 99.8% and 97.2% in the presence of inflammation when ceftaroline 600 mg was administered every 8 h and every 12 h, respectively [ 70 ].…”

Section: Beta-lactam Antibioticsmentioning

confidence: 99%

The Blood–Brain Barrier and Pharmacokinetic/Pharmacodynamic Optimization of Antibiotics for the Treatment of Central Nervous System Infections in Adults

Haddad

Carr

Balian³

et al. 2022

Antibiotics

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Bacterial central nervous system (CNS) infections are serious and carry significant morbidity and mortality. They encompass many syndromes, the most common being meningitis, which may occur spontaneously or as a consequence of neurosurgical procedures. Many classes of antimicrobials are in clinical use for therapy of CNS infections, some with established roles and indications, others with experimental reporting based on case studies or small series. This review delves into the specifics of the commonly utilized antibacterial agents, updating their therapeutic use in CNS infections from the pharmacokinetic and pharmacodynamic perspectives, with a focus on the optimization of dosing and route of administration that have been described to achieve good clinical outcomes. We also provide a concise synopsis regarding the most focused, clinically relevant information as pertains to each class and subclass of antimicrobial therapeutics. CNS infection morbidity and mortality remain high, and aggressive management is critical in ensuring favorable patient outcomes while averting toxicity and upholding patient safety.

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“…Chauzy et al reported a mean of 9% in a series of 11 patients with external ventricular drain, but without meningeal inflammation [ 8 ]. However, this penetration can be enhanced with meningeal inflammation, as showed by Helfer et alt [ 9 ]. In fact, animal models of meningitis show variable rates from 15 to 51%.…”

Section: Casementioning

confidence: 99%

Use of ceftaroline in complex central nervous system infections

Alonso Álvarez,

Sánchez Vidal,

Ramos Merino

et al. 2023

Rev Esp Quimioter

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Population Pharmacokinetic Modeling and Probability of Target Attainment of Ceftaroline in Brain and Soft Tissues

Cited by 12 publications

References 47 publications

Impact of Key Components of Intensified Ceftaroline Dosing on Pharmacokinetic/Pharmacodynamic Target Attainment

Impact of Key Components of Intensified Ceftaroline Dosing on Pharmacokinetic/Pharmacodynamic Target Attainment

The Blood–Brain Barrier and Pharmacokinetic/Pharmacodynamic Optimization of Antibiotics for the Treatment of Central Nervous System Infections in Adults

Use of ceftaroline in complex central nervous system infections

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