Probability of pharmacological target attainment with flucloxacillin in <i>Staphylococcus aureus</i> bloodstream infection: a prospective cohort study of unbound plasma and individual MICs

Moser, Stephan; Rehm, Sophia; Guertler, Nicolas; Hinić, Vladimira; Dräger, Sarah; Bassetti, Stefano; Rentsch, Katharina; Sendi, Parham; Osthoff, Michael

doi:10.1093/jac/dkab089

Cited by 18 publications

(14 citation statements)

References 28 publications

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“…25 Recent pharmacologic studies showed that in a majority of patients, a reduction of the flucloxacillin dose would still lead to attainment of the optimal pharmacodynamic endpoint. 26,27 Also, our study and other reports suggest an increased risk of adverse events with a higher flucloxacillin dose and flucloxacillin concentration. 27,28 Although the flucloxacillin concentration measurements in our study were limited, Figure 1A…”

Section: Discussionsupporting

confidence: 73%

Hypokalaemia in patients treated with intravenous flucloxacillin: Incidence and risk factors

Leegwater

Westgeest

Schippers

et al. 2022

Brit J Clinical Pharma

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Introduction Hypokalaemia is a potentially life‐threatening adverse event of flucloxacillin with unknown incidence. The risk of flucloxacillin‐induced hypokalaemia has recently been suggested to be increased among females compared to males. The aim of this study is to describe the incidence and to determine the influence of sex and other risk factors on flucloxacillin‐induced hypokalaemia. Methods A retrospective single‐centre cohort study was performed. Patients treated with intravenous flucloxacillin for >24 hours between January 2017 and October 2020, a baseline potassium level of ≥3.5 mmol/L and potassium measurement during treatment were included. The primary endpoint was incidence of hypokalaemia defined as the percentage of patients with a potassium measurement <3.5 mmol/L during flucloxacillin treatment. Logistic regression modelling was used to establish risk factors for hypokalaemia. Results A total of 835 patients were included, 58.2% male and median age 71.0 years (interquartile range 61.0‐81.0). The incidence of hypokalaemia was 23.7% (28.4% in females vs 20.4% in males). A dose‐dependent relation between sex and the incidence of hypokalaemia was found. The risk of hypokalaemia was 4.41 (95% confidence interval 1.47‐13.24) times higher in females compared to males when receiving a flucloxacillin dose of >8 g/24 h. No sex differences were found for lower daily doses. Other risk factors for hypokalaemia were older age, concomitant antibiotic use, lower bodyweight, lower baseline plasma potassium concentration and longer treatment duration. Conclusion Hypokalaemia is a frequent complication in patients treated with intravenous flucloxacillin. Females receiving >8 g intravenous flucloxacillin per day are more prone to develop hypokalaemia compared to males.

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Section: Discussionsupporting

confidence: 73%

Hypokalaemia in patients treated with intravenous flucloxacillin: Incidence and risk factors

Leegwater

Westgeest

Schippers

et al. 2022

Brit J Clinical Pharma

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“…This problem is minimized in animal infection model or dynamic in vitro infection model studies aimed at elucidating the predictive PK-PD index and target values for various magnitudes of bacterial kill by ensuring that several bacterial strains are included in the study to inform setting of PK-PD targets and breakpoints (Zhao et al, 2016;Mouton et al, 2018b;Jorda and Zeitlinger, 2020). However, an inaccurate estimate from a single determination of MIC for an isolate from a particular patient is problematic in the clinical application of MIC-based PK-PD targets within the framework of what has been described as therapeutic drug monitoring (TDM) (Mouton et al, 2018b;Roberts et al, 2019;Märtson et al, 2020;Seeger et al, 2021a;Goutelle et al, 2021;Jorgensen et al, 2021;Moser et al, 2021). Thus, if an isolate from an infected patient returns an MIC estimate from an assay which has a typical error range of two dilutions (i.e., potentially a 4-fold range of reported MIC values), it follows that the PK-PD driven target plasma concentration for that patient would vary 4-fold if the PK-PD index for the antibiotic is fAUC/MIC or fC max /MIC.…”

Section: Mic: a Highly Problematic Measure Of Antibacterial Pd Activitymentioning

confidence: 99%

Limitations of Antibiotic MIC-Based PK-PD Metrics: Looking Back to Move Forward

Landersdorfer

Nation

2021

Front. Pharmacol.

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Within a few years after the first successful clinical use of penicillin, investigations were conducted in animal infection models to explore a range of factors that were considered likely to influence the antibacterial response to the drug. Those studies identified that the response was influenced by not only the total daily dose but also the interval between individual doses across the day, and whether penicillin was administered in an intermittent or continuous manner. Later, as more antibiotics were discovered and developed, antimicrobial pharmacologists began to measure antibiotic concentrations in biological fluids. This enabled the linking of antibacterial response at a single time point in an animal or in vitro infection model with one of three summary pharmacokinetic (PK) measures of in vivo exposure to the antibiotic. The summary PK exposure measures were normalised to the minimum inhibitory concentration (MIC), an in vitro measure of the pharmacodynamic (PD) potency of the drug. The three PK-PD indices (ratio of maximum concentration to MIC, ratio of area under the concentration-time curve to MIC, time concentration is above MIC) have been used extensively since the 1980s. While these MIC-based summary PK-PD metrics have undoubtedly facilitated the development of new antibiotics and the clinical application of both new and old antibiotics, it is increasingly recognised that they have a number of substantial limitations. In this article we use a historical perspective to review the origins of the three traditional PK-PD indices before exploring in detail their limitations and the implications arising from those limitations. Finally, in the interests of improving antibiotic development and dosing in patients, we consider a model-based approach of linking the full time-course of antibiotic concentrations with that of the antibacterial response. Such an approach enables incorporation of other factors that can influence treatment outcome in patients and has the potential to drive model-informed precision dosing of antibiotics into the future.

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“…The values found for the MICs are in line with the values reported previously in literature, however large distributions are lacking. A study in 37 MSSA isolates reported values between 0.06 and 0.25 mg/L [ 9 ], while in case reports, higher values for the flucloxacillin MIC were reported of up to 1 mg/L [ 10 , 11 ]. Because of the lack of data on MIC distribution for flucloxacillin, several studies use MIC values for oxacillin instead with an ECOFF of 2 mg/L [ 12 , 13 , 14 , 15 ].…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamics of Flucloxacillin in a Neutropenic Murine Thigh Infection Model: A Piece of the Puzzle towards Evidence-Based Dosing

et al. 2022

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For decades, flucloxacillin has been used to treat methicillin-susceptible Staphylococcus aureus (MSSA). Little is still known about its pharmacodynamics (PD). The present study aimed to determine the pharmacokinetic (PK)/PD index and the PD-index value minimally required for efficacy. MICs of 305 MSSA isolates were measured to determine the wild-type distribution. The PD of 8 S. aureus, 1 S. pyogenes, and 1 S. agalactiae isolates were evaluated in a neutropenic murine thigh infection model. Two S. aureus isolates were used in a dose-fractionation study and a dose–response analysis was performed additionally in the in vivo model. Data were analyzed with a population PK and sigmoid maximum effect model. The end of the wild-type distribution was 1 mg/L. The percentage of time the unbound concentration was above MIC (%fT > MIC) was best correlated with efficacy. For S. aureus, median %fT > 0.25 × MIC required for 1-log reduction was 15%. The value for S. pyogenes was 10%fT > MIC and for S. agalactiae 22%fT > 0.25xMIC for a 1-log reduction. The effect of flucloxacillin reached a 2-log reduction of S. aureus at 20%fT > 0.25xMIC and also for S. pyogenes and S. agalactiae, a reduction was reached. These data may serve to optimize dosing regimens currently used in humans.

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Probability of pharmacological target attainment with flucloxacillin in Staphylococcus aureus bloodstream infection: a prospective cohort study of unbound plasma and individual MICs

Cited by 18 publications

References 28 publications

Hypokalaemia in patients treated with intravenous flucloxacillin: Incidence and risk factors

Hypokalaemia in patients treated with intravenous flucloxacillin: Incidence and risk factors

Limitations of Antibiotic MIC-Based PK-PD Metrics: Looking Back to Move Forward

Pharmacodynamics of Flucloxacillin in a Neutropenic Murine Thigh Infection Model: A Piece of the Puzzle towards Evidence-Based Dosing

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