Stephan Moser1, Sophia Rehm2, Nicolas Guertler1, Vladimira Hinic3, Sarah Dräger1, Stefano Bassetti1, Katharina M Rentsch2, Parham Sendi4,5, Michael Osthoff1,6. 1. Division of Internal Medicine, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland. 2. Department of Laboratory Medicine, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland. 3. Division of Clinical Bacteriology and Mycology, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland. 4. Department of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland. 5. Institute for Infectious Diseases, University of Bern, Friedbühlstrasse 51, 3001 Bern, Switzerland. 6. Department of Clinical Research, University of Basel, Schanzenstrasse 55, 4056, Basel, Switzerland.
Abstract
OBJECTIVES: MSSA bloodstream infections (BSIs) are associated with considerable mortality. Data regarding therapeutic drug monitoring (TDM) and pharmacological target attainment of the β-lactam flucloxacillin are scarce. PATIENTS AND METHODS: We determined the achievement of pharmacokinetic/pharmacodynamic targets and its association with clinical outcome and potential toxicity in a prospective cohort of 50 patients with MSSA-BSI. Strain-specific MICs and unbound plasma flucloxacillin concentrations (at five different timepoints) were determined by broth microdilution and HPLC-MS, respectively. RESULTS: In our study population, 48% were critically ill and the 30 day mortality rate was 16%. The median flucloxacillin MIC was 0.125 mg/L. The median unbound trough concentration was 1.7 (IQR 0.4-9.3), 1.9 (IQR 0.4-6.2) and 1.0 (IQR 0.6-3.4) mg/L on study day 1, 3 and 7, respectively. Optimal (100% fT>MIC) and maximum (100% fT>4×MIC) target attainment was achieved in 45 (90%) and 34 (68%) patients, respectively, throughout the study period. Conversely, when using the EUCAST epidemiological cut-off value instead of strain-specific MICs, target attainment was achieved in only 13 (26%) patients. The mean unbound flucloxacillin trough concentration per patient was associated with neurotoxicity (OR 1.12 per 1 mg/L increase, P = 0.02) and significantly higher in deceased patients (median 14.8 versus 1.7 mg/L, P = 0.01). CONCLUSIONS: Flucloxacillin pharmacological target attainment in MSSA-BSI patients is frequently achieved when unbound flucloxacillin concentrations and strain-specific MICs are considered. However, currently recommended dosing regimens may expose patients to excessive flucloxacillin concentrations, potentially resulting in drug-related organ damage.
OBJECTIVES: MSSA bloodstream infections (BSIs) are associated with considerable mortality. Data regarding therapeutic drug monitoring (TDM) and pharmacological target attainment of the β-lactam flucloxacillin are scarce. PATIENTS AND METHODS: We determined the achievement of pharmacokinetic/pharmacodynamic targets and its association with clinical outcome and potential toxicity in a prospective cohort of 50 patients with MSSA-BSI. Strain-specific MICs and unbound plasma flucloxacillin concentrations (at five different timepoints) were determined by broth microdilution and HPLC-MS, respectively. RESULTS: In our study population, 48% were critically ill and the 30 day mortality rate was 16%. The median flucloxacillin MIC was 0.125 mg/L. The median unbound trough concentration was 1.7 (IQR 0.4-9.3), 1.9 (IQR 0.4-6.2) and 1.0 (IQR 0.6-3.4) mg/L on study day 1, 3 and 7, respectively. Optimal (100% fT>MIC) and maximum (100% fT>4×MIC) target attainment was achieved in 45 (90%) and 34 (68%) patients, respectively, throughout the study period. Conversely, when using the EUCAST epidemiological cut-off value instead of strain-specific MICs, target attainment was achieved in only 13 (26%) patients. The mean unbound flucloxacillin trough concentration per patient was associated with neurotoxicity (OR 1.12 per 1 mg/L increase, P = 0.02) and significantly higher in deceased patients (median 14.8 versus 1.7 mg/L, P = 0.01). CONCLUSIONS:Flucloxacillin pharmacological target attainment in MSSA-BSI patients is frequently achieved when unbound flucloxacillin concentrations and strain-specific MICs are considered. However, currently recommended dosing regimens may expose patients to excessive flucloxacillin concentrations, potentially resulting in drug-related organ damage.
Authors: Eveline Wallenburg; Rob Ter Heine; Dylan W de Lange; Henk van Leeuwen; Jeroen A Schouten; Jaap Ten Oever; Eva Kolwijck; David M Burger; Peter Pickkers; Emilie M Gieling; Monique M de Maat; Tim Frenzel; Roger J Brüggemann Journal: J Antimicrob Chemother Date: 2021-11-12 Impact factor: 5.790
Authors: Eveline E Roelofsen; Brenda C M de Winter; Heleen van der Spek; Susan Snijders; Birgit C P Koch; Sanne van den Berg; Anouk E Muller Journal: Antibiotics (Basel) Date: 2022-08-03