A Population Pharmacokinetic Analysis of Continuous Infusion of Cloxacillin during Staphylococcus aureus Bone and Joint Infections

Abstract

Intravenous administration of antibiotics is recommended during the early phase of methicillin-susceptible S. aureus (MSSA) bone and joint infection (BJI). We sought to compare the plasma concentrations of cloxacillin administered alternately by continuous and intermittent infusion (CI and ItI) in patients with MSSA BJI. In this prospective crossover trial, patients were randomly assigned to receive either 3 days of CI (two 75-mg/kg 12-h cloxacillin infusions per day) and then 3 days of ItI (four 37.5-mg/kg 1-h cloxacillin infusions per day) or vice versa. The drug concentration measurement was performed on day 3 of each type of administration at 1, 6, and 11 h and at 1, 2, 3, 4, and 6 h after the beginning of CI and ItI, respectively. We used the nonparametric algorithm NPAG to estimate population pharmacokinetic (PK) parameters. The final model was used to perform pharmacokinetic/pharmacodynamic (PK/PD) simulations and calculate the probabilities of target attainment (PTA) for several ItI and CI dosing regimens. We considered two PK/PD targets of time spent above the MIC for free cloxacillin concentrations (fT>MIC): 50 and 100%. Eighty-four concentrations from 11 patients were analyzed. A two-compartment model adequately described the data. ItI with q6h regimens and short 1-h infusions of 2,000 or 3,000 mg were associated with low PTA, even for the low target (50% fT>MIC) while 3-h infusions and continuous infusions (6 to 12 g/day) were associated with a PTA of >90% for an MIC up to 0.5 mg/liter. These results support the use of prolonged or continuous infusion of cloxacillin in patients with BJI.

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

“…Variations in MIC determinations have to be considered for the definition of pharmacological targets and dosing adjustments guided by therapeutic drug monitoring. 21 However, the fact that MSSA MICs in the present and previous studies 22 were considerably lower than 2 mg/L implies that the use of ECOFF to define optimal target flucloxacillin concentration is imprecise, as there is a risk of exposing patients to higher and potentially toxic drug concentrations. In our strain population, the flucloxacillin MIC distribution closely resembles that of cloxacillin rather than oxacillin.…”

“…The probability of optimal target attainment (100% fT >0.5 mg/L ) with a cloxacillin dosage of 2 g every 4 and 6 h was only 38% and 9%, respectively, when protein binding of 95% was assumed. 22 Conversely, our results demonstrate 90% target attainment when we used the measured unbound flucloxacillin plasma concentration. Similarly, pharmacological target attainment (50% fT >2 mg/L ) with a flucloxacillin dosage of 2 g every 4 h was only 10% in the study of Landersdorfer et al ., 23 which again did not account for the variation in protein binding, whereas our results demonstrate 70%–80% target attainment for the same dosing regimen.…”

“…Previously, more aggressive dosing recommendations have been made based on total flucloxacillin concentrations or the oxacillin ECOFF. 10 , 20 , 22 The present data showing high target achievement with the use of the strain-specific MIC, as well as the lack of association between outcome and target achievement with the use of MSSA ECOFF, challenge current flucloxacillin dosing recommendations. In addition, dosages should only be adjusted according to the measured unbound flucloxacillin concentration in patients with MSSA-BSI, 20 as models that are able to accurately predict the unbound concentration from the total measured flucloxacillin concentration are lacking.…”

Model-Informed Precision Dosing of Antibiotics in Osteoarticular Infections

“…Courjon et al 36 recruited 11 patients with OAI caused by MSSA who received continuous infusion (CI) or intermittent infusion (II) of cloxacillin using a prospective crossover design and developed a PPK model. Tables 1 and 2 summarize the demographic data of patients and model parameters.…”

Parametric and Nonparametric Methods in Population Pharmacokinetics: Experts’ Discussion on Use, Strengths, and Limitations

“…As an example, Tables 1 and 2 show the typical results obtained after the analysis with a P and an NP program, for the same real data set from a previously published study 4 …”