TY  - JOUR
A1  - Busse, David
A1  - Simon, Philipp
A1  - Petroff, David
A1  - El-Najjar, Nahed
A1  - Schmitt, Lisa
A1  - Bindellini, Davide
A1  - Dietrich, Arne
A1  - Zeitlinger, Markus
A1  - Huisinga, Wilhelm
A1  - Michelet, Robin
A1  - Wrigge, Hermann
A1  - Kloft, Charlotte
T1  - High-dosage fosfomycin results in adequate plasma and target-site exposure in morbidly obese and nonobese nonhyperfiltration patients
T2  - Antimicrobial agents and chemotherapy
N2  - The objectives of this study were the identification in (morbidly) obese and nonobese patients of (i) the most appropriate body size descriptor for fosfomycin dose adjustments and (ii) adequacy of the currently employed dosing regimens. Plasma and target site (interstitial fluid of subcutaneous adipose tissue) concentrations after fosfomycin administration (8 g) to 30 surgery patients (15 obese/15 nonobese) were obtained from a prospective clinical trial. After characterization of plasma and microdialysis-derived target site pharmacokinetics via population analysis, short-term infusions of fosfomycin 3 to 4 times daily were simulated. The adequacy of therapy was assessed by probability of pharmacokinetic/pharmacodynamic target attainment (PTA) analysis based on the unbound drug-related targets of an %fT(>= MIC) (the fraction of time that unbound fosfomycin concentrations exceed the MIC during 24 h) of 70 and an fAUC(0-24h)/MIC (the area under the concentration-time curve from 0 to 24 h for the unbound fraction of fosfomycin relative to the MIC) of 40.8 to 83.3. Lean body weight, fat mass, and creatinine clearance calculated via adjusted body weight (ABW) (CLCRCG_ABW) of all patients (body mass index [BMI] = 20.1 to 52.0 kg/m(2)) explained a considerable proportion of between-patient pharmacokinetic variability (up to 31.0% relative reduction). The steady-state unbound target site/plasma concentration ratio was 26.3% lower in (morbidly) obese than nonobese patients. For infections with fosfomycin-susceptible pathogens (MIC <= 16 mg/L), intermittent "high-dosage" intravenous (i.v.) fosfomycin (8 g, three times daily) was sufficient to treat patients with a CLCRCG_ABW of,130 mL/min, irrespective of the pharmacokinetic/pharmacodynamic indices considered. For infections by Pseudomonas aeruginosa with a MIC of 32 mg/L, when the index fAUC0-24h/MIC is applied, fosfomycin might represent a promising treatment option in obese and nonobese patients, especially in combination therapy to complement beta-lactams, in which carbapenem-resistant P. aeruginosa is critical. In conclusion, fosfomycin showed excellent target site penetration in obese and nonobese patients. Dosing should be guided by renal function rather than obesity status.
KW  - population pharmacokinetics
KW  - pharmacodynamics
KW  - fosfomycin
KW  - obesity
KW  - adipose tissue
KW  - interstitial space fluid
KW  - microdialysis
KW  - anti-infective
KW  - probability of target attainment
Y1  - 2022
UR  - https://publishup.uni-potsdam.de/frontdoor/index/index/docId/64201
SN  - 0066-4804
SN  - 1098-6596
VL  - 66
IS  - 6
PB  - American Society for Microbiology
CY  - Washington
ER  -