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.
KEYWORDS: cloxacillin, continuous infusion, pharmacokinetics, pharmacodynamic, antibiotics, bone and joint infections, osteomyelitis, Staphylococcus aureus, population PK analysis, penicillin, population pharmacokinetics
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.
INTRODUCTION
Staphylococcus aureus is the main causative pathogen involved in bone and joint infections (BJI) (1). Despite the increasing use of the oral route during the main phase of the antibiotic treatment, intravenous antibiotic administration is still recommended in the early phase of management (1). Thus, for methicillin-susceptible S. aureus (MSSA) BJI, isoxazolyl penicillin cloxacillin can be used for 5 to 14 days depending on the type of BJI and the related guidelines. Similar to other β-lactams, the bactericidal pattern of penicillins is time dependent (2). With the half-life of cloxacillin being close to 45 min, administration needs to be repeated four to six times per day. Continuous infusion (CI) of β-lactams is associated with an improvement in pharmacokinetic/pharmacodynamic (PK/PD) in vitro measures and a potentially improved clinical outcome, especially when used in critically ill patients presenting with sepsis (3).
The CI of isoxazolyl penicillin is poorly reported. One study has reported a higher probability of target attainment (PTA) with CI of flucloxacillin compared to intermittent infusion (ItI) (4). Other data are represented by retrospective clinical studies without pharmacological data (5). Several teams use cloxacillin CI, but its usefulness and reliability need to be described more precisely. No previous cloxacillin pharmacodynamic profiling has been published in the context of BJI. We report here the results of a prospective study comparing cloxacillin plasma concentrations in patients with MSSA BJI alternately receiving a CI and an ItI. We sought in the present study to (i) compare cloxacillin exposure during CI and ItI, (ii) perform a population PK analysis, and (iii) characterize the most appropriate dosage and type of administration in order to optimize PTA according to common PK-PD targets for β-lactams.
RESULTS
Between November 2017 and September 2018, 12 patients were included in the study, including 9 men. One patient did not complete the study because of gastrointestinal side effects and infusion phlebitis. Eventually, 5 patients in the CI/ItI group and 6 in the ItI/CI group completed the 6-day course of the study and were included in the final analysis. The median age (range) of the participants was 53 (21 to 65) years, with median body weights of 83 (52 to 95) kg in the CI/ItI group and 70 (60 to 97) kg in the ItI/CI group. Median (minimum to maximum) body surface area (BSA) was 1.82 (1.54 to 2.21) m2. Six patients suffered device-related BJI, three had vertebral osteomyelitis (two had bacteremia), one had septic arthritis, and one had chronic osteomyelitis. The mean glomerular filtration rates were 105 (61 to 120) ml/min/1.73 m2 and 105 (73 to 126) ml/min/1.73 m2 in the CI/ItI and ItI/CI groups, respectively. Among the 12 patients initially included in the study, 4 had infusion phlebitis (3 during ItI), and 1 of the four patients also had grade 2 nausea, leading him to drop out of the study. Two other patients suffered grade 1 diarrhea.
The median cloxacillin MIC value was 0.38 (0.125 to 0.5) mg/liter. The evolution of the total cloxacillin plasma concentrations after infusion for ItI and during infusion for CI is reported in Fig. 1. With regard to individual data, using the free-drug concentrations and the measured MICs for each patient, fT>MIC during CI (mean, 100%) was superior to ItI (mean, 88.9%; P = 0.0078). Of note, four measured concentrations were discarded from the analysis because the samples were collected through the administration site by mistake. The corresponding measured concentrations were very high and not realistic, with a difference from the mean of the other concentrations obtained at the same time of >10 standard deviations.
FIG 1.
Total cloxacillin plasma concentrations: during intermittent infusion (ItI) (A) and during continuous infusion (CI) (B). Points and error bar represent means and standard deviations, respectively.
A two-compartment model best fit the data. Cloxacillin total body clearance (CL), central volume of distribution (V1) and peripheral volume of distribution (V2) were set as random parameters. The value of the intercompartment clearance (Q) was set at the same fixed value in all subjects, this value being estimated by the algorithm, because its variability could not be well estimated.
BSA was found to correlate positively with cloxacillin V1 and was the only covariate included in the final model. The parameter estimates of the final model are summarized in Table 1. Individual PK parameters (Bayesian posterior estimates) are presented in Table 2. The model adequately fit the data, as shown in Fig. 2. The model tends to underestimate the peak concentrations of cloxacillin, but this slight bias was supported by the error model, as shown in the plots of weighted residuals (Fig. 2). The internal validation of the model was acceptable, as shown in the visual predictive check available in the supplemental material (see Fig. S1).
TABLE 1.
Summary of population pharmacokinetic parameters of cloxacillin
| Parameter | Mean | Median | CVb (%) | Variancec |
|---|---|---|---|---|
| CL (liters/h) | 16.2 | 15.6 | 25.5 | 16.9 |
| V1 (liters/1.73 m²)a | 16.0 | 13.6 | 39.0 | 39.2 |
| V2 (liters) | 2.7 | 2.2 | 57.7 | 2.4 |
| Q (liters/h, fixed) | 2.1 |
The relationship between individual V1 (V1i) and individual body surface area (BSAi) was determined as follows: V1i = V1 × (BSAi/1.73).
CV, coefficient of variation.
Estimated correlation coefficients between parameters were as follows: CL and V1, 0.81; CL and V2, 0.58 V1 and V2, 0.43.
TABLE 2.
Individual PK parameter values (Bayesian posterior estimates) of cloxacillin in 11 patients
| Parametera | Mean (SD) | Median (range) |
|---|---|---|
| CL (liters/h) | 16.2 (4.3) | 15.6 (11.1–22.9) |
| V1 (liters) | 17.4 (7.6) | 16.1 (9.0–35.5) |
| Total V (liters) | 20.1 (8.4) | 17.7 (10.7–40.3) |
| kel (h−1) | 1.00 (0.28) | 0.96 (0.65–1.53) |
| t1/2 (h) | 1.26 (0.45) | 1.18 (0.78–1.95) |
CL, total body clearance; kel, elimination rate constant; t1/2, terminal half-life; V1, central volume of distribution; total V, total volume of distribution. The kel and t1/2 values were derived from individual estimates of clearance and volume parameters.
FIG 2.
Predictive performance of the final population model of cloxacillin. (Left) Observed cloxacillin concentrations versus model-based predictions. Open blue circles, population predictions (R2 = 0.86); red filled circles, individual predictions (R2 = 0.95). The dashed line is the line of identity. (Right) Weighted residuals (prediction minus observation) versus individual predictions.
PTA is displayed as a function of the MIC for various intermittent and continuous dosage regimens simulated in 2,000 patients in Fig. 3. The results are detailed for the MIC epidemiological cutoff (0.5 mg/liter) in Table 3. BSA showed a marginal influence on the PK/PD index and PTA. For example, for the 2,000-mg q6h, 1-h infusion regimen, the median fT>MIC values were 47, 50, 53, and 56% for BSA values of 1.5, 1.75, 2, and 2.25 m2, respectively, and the associated PTA values were all suboptimal for an MIC of 0.5 mg/liter. PTA values varied with both the dosage regimen and the target considered. For the traditional target of 50% fT>MIC, intermittent regimens with short 1-h infusions of 2,000 or 3,000 mg were associated with insufficient PTA, except for 2,000 mg q4h. However, increasing the infusion duration to 3 h resulted in acceptable PTA for MIC values up to 0.5 mg/liter for the q6h regimens. All continuous infusion regimens evaluated were associated with a PTA of 100%, which was expected, since these regimens are associated with 100% fT>MIC. For the high target of 100% fT>MIC, all intermittent infusion regimens were associated with a PTA of <90%, whereas all continuous infusion regimens provided acceptable PTA.
FIG 3.
Probability of target attainment for various simulated cloxacillin dosage regimens. The PK/PD targets are 50% fT>MIC (upper panel) and 100% fT>MIC (lower panel). CI, continuous infusion; IT, infusion time; PTA, probability of target attainment.
TABLE 3.
PK/PD objectives and probability of target attainment for various cloxacillin dosage regimens simulated in 2,000 patientsa
| Cloxacillin daily dosage (mg), interval | Infusion time (h) | Median fT>MIC (95% CI)b | PTAc for: |
|
|---|---|---|---|---|
| 50% fT>MIC | 100% fT>MIC | |||
| 2,000, q6h | 1 | 0.50 (0.39–0.73) | 0.50 | 0 |
| 2,000, q6h | 2 | 0.59 (0.49–0.82) | 0.96 | 0 |
| 2,000, q6h | 3 | 0.70 (0.61–0.93) | 1 | 0 |
| 2,000, q6h | 4 | 0.83 (0.73–1) | 1 | 0.09 |
| 3,000, q6h | 1 | 0.60 (0.45–0.84) | 0.88 | 0 |
| 3,000, q6h | 2 | 0.69 (0.56–0.93) | 1 | 0 |
| 3,000, q6h | 3 | 0.80 (0.68–1) | 1 | 0.07 |
| 3,000, q6h | 4 | 0.92 (0.81–1) | 1 | 0.29 |
| 2,000, q4h | 1 | 0.78 (0.60–1) | 1 | 0.15 |
| 2,000, q4h | 2 | 0.94 (0.76–1) | 1 | 0.38 |
| 6,000 | Continuous | 1 | 1 | 1 |
| 8,000 | Continuous | 1 | 1 | 1 |
| 10,000 | Continuous | 1 | 1 | 1 |
| 12,000 | Continuous | 1 | 1 | 1 |
The results are given for an MIC of 0.5 mg/liter and a BSA of 1.75 m2. q6h, every 6 h; q4h, every 4 h.
95% CI, 95% confidence interval.
PTA, probability of target attainment.
DISCUSSION
Based on a prospective crossover designed trial including patients with MSSA BJI, this is the first study providing a population PK analysis of cloxacillin. Our study results support the value of prolonged and continuous infusion of cloxacillin to optimize the achievement of PK/PD targets. In order to achieve 100% fT>MIC for MIC up to 0.5 mg/liter, CI is required. Of note, a dose as low as 6,000 mg/24 h administered by CI is sufficient to achieve this goal. For achieving a target of 50% fT>MIC, both CI and prolonged ItI were associated with acceptable PTA. Interestingly, 3-h ItI of 2,000 and 3,000 mg administered q6h provided PTA results for this target similar to CIs of 8,000 and 12,000 mg, respectively. It is noteworthy that the Clinical and Laboratory Standards Institute (CLSI) or European Committee on Antimicrobial Susceptibility Testing (EUCAST) oxacillin breakpoint for MSSA is ≤2 mg/liter. For such MICs, even a CI of 12,000 mg does not provide satisfactory PTA. Increasing the daily dose of cloxacillin could be a means of increasing the PTA for MICs beyond the epidemiological cutoff, but then the risk of acute kidney injury should rise (6). ItI with q4h regimens allowed a PTA of >90% for the low target (50% fT>MIC); however, this procedure is more time-consuming for the nurses and can be embarrassing for the patients, since some infusions have to be performed during the night.
Our results are in accordance with the population PK analysis of flucloxacillin published by Landersdorfer et al. (4). Both antibiotics share similar characteristics: they are highly bound proteins drugs with a short half-life. Flucloxacillin showed a high PTA for MICs up to 0.75 to 1 mg/liter (a PTA of 86% at 1 mg/liter) for a continuous or a prolonged (4-h) infusion of 6 g/day. Taken together, these data favor the use of cloxacillin CI for severe infections such S. aureus bacteremia, which is common during BJI (7), especially pyogenic vertebral osteomyelitis (8), or when antibiotic diffusion into the infected tissue is limited as in BJI.
Therefore, the results of our dosing simulation may not hold true in other groups of patients with severe renal impairment or increased renal clearance.
Infusion phlebitis was common during ItI and was probably linked to the high concentration of cloxacillin when reconstituted in only 50 ml, together with a 1-h administration. This procedure was required to rigorously compare both types of administration since the stability of an antibiotic is related to its concentration (9), but cloxacillin is usually reconstituted in larger volumes when ItI is used.
Our results support the increased 30-day microbiological cure rate of patients with S. aureus infective endocarditis treated with a CI of oxacillin compared to that of patients treated with an ItI of oxacillin reported in a retrospective study (5). In another retrospective study that included critically ill patients, Verdier et al. showed that median plateau values measured during the CI of cloxacillin (n = 17) were higher than the median trough values measured during ItI (n = 51) for patients with normal creatinine clearance (32.4 versus 14.5 mg/liter) and patients with reduced creatinine clearance (67.1 versus 32.9 mg/liter) (10). High trough concentrations of cloxacillin have been associated with neurological impairment in intensive care unit (ICU) patients, especially in patients with low creatinine clearance (<10 ml/min) (11). Therefore, CI should be used with caution in such patients. In critically ill patients with hypoabuminemia and without severe renal dysfunction, the highly protein-bound flucloxacillin (95 to 97%) volume of distribution is increased 2-fold. Monte-Carlo simulations suggested that, unlike ItI, CI would enable successful attainment of targets, such as 50% fT>MIC and even 100% fT>4×MIC, depending on the daily dose used (12). Our results regarding cloxacillin CI are arguably valid for methicillin-susceptible coagulase-negative staphylococci often involved in prosthetic joint infections (13) since the EUCAST breakpoint for cloxacillin susceptibility is ≤0.25 mg/liter (6). Other benefits of CI, such as lower cost, the ability to simplify outpatient parenteral antimicrobial therapy, or the ability to reduce the workload of the nurse, should also be considered but were not recorded in our study.
The limited sample size is a limitation of our study. Therefore, the population PK analysis may have underestimated the interindividual PK variability. Cloxacillin, like flucloxacillin, is known to be mainly excreted unchanged by the kidneys. Surprisingly, renal function was not identified as a significant covariate in our population analysis. We think that this was due to the limited range of renal function in the patients included. Moreover, ICU management of the infection, which is frequently associated with a decrease of albuminemia levels (14) and can also be associated with an increased renal clearance, was an exclusion criterion, so therapeutic drug monitoring could be useful in such clinical settings. We assumed fixed protein binding of 95% for cloxacillin, based on available data that are scarce and limited. It also acknowledged that the optimal target value of fT>MIC is uncertain in patients with BJI. Achieving 100% fT>MIC may not be necessary in all patients. Further research is required to clarify this question.
Finally, the CI of cloxacillin can be used safely at the early phase of MSSA BJI and is associated with an improvement in PK/PD parameters compared to ItI at the same daily dose. The small reconstitution volume of 50 ml applied in this study should not be used for cloxacillin doses greater than 6 g when CI is used because of infusion phlebitis risks. This precaution has to be considered in order to choose the appropriate volume of the elastomeric pump if outpatient parenteral antibiotic therapy is prescribed.
MATERIALS AND METHODS
Design and inclusion criteria.
This prospective, crossover designed trial was performed in the 28-bed infectious diseases ward of the University Hospital of Nice, France, between November 2017 and September 2018. The local ethics committee (Sud Méditerranée V) and the French National Agency for the Safety of Medicines and Health Products (ANSM) approved the study (registration number 160802A-43).
All adult patients admitted for monomicrobial MSSA BJI were eligible. The microbiological diagnosis was based on cultures of specimens obtained either intraoperatively or preoperatively by computed tomography-guided aspiration or on blood cultures (for vertebral osteomyelitis). The exclusion criteria included pregnancy, history of β-lactam allergy, chronic kidney disease (CKD-EPI < 30 ml/min/1.73 m2), liver failure, methotrexate intake, type M penicillin intake within 36 h before inclusion, and ICU hospitalization before admission. Eligible participants provided written informed consent, and 12 patients were randomly assigned to receive via peripheral vein either 3 days of CI and then 3 days of ItI (group CI/ItI) or vice versa (group ItI/CI).
Patients’ characteristics, type of BJI, and MIC determination.
The following characteristics of patients were collected: gender, age, weight, type of BJI (spondylodiscitis, septic arthritis of native joint, prosthetic joint infection, and osteomyelitis), and underlying immunosuppression and drug intake. Renal clearance (CKD-EPI), C-reactive protein (CRP), aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP), and bilirubin assessments and a hemogram were performed on days 0, 3, and 6.
Cloxacillin MIC for each strain was determined by Etest (catalog no. 92044; Liofilchem Srl, Roseto degli Abruzzi, Italy). According to EUCAST recommendations, S. aureus strains were considered to be susceptible to methicillin with an MIC of ≤2 mg/liter and resistant with an MIC of >2 mg/liter (15).
Cloxacillin administration, plasma sampling, and drug assay.
Patients were randomly assigned to receive via peripheral vein either 3 days of two 75-mg/kg 12-h cloxacillin infusions per day and then 3 days of four 37.5-mg/kg 1-h cloxacillin infusions per day (group CI/ItI) or vice versa (group ItI/CI). Patients beginning with the CI were administered a loading dose of 37.5 mg/kg cloxacillin for 1 h, and in these patients the total daily dose remained at 150 mg/kg during day 1. During CI, 75 mg/kg cloxacillin was reconstituted with 50 ml of 0.09% sodium chloride (Luer-Lok 50-ml syringe; BD Plastipak; Becton Dickinson, Franklin Lakes, NJ) and administered for 12 h with a syringe pump. During ItI, 37.5 mg/kg cloxacillin was also reconstituted with 50 ml of 0.09% sodium chloride and administered for 1 h with a syringe pump. Since the ANSM did not allow off-label use of cloxacillin for the study, the maximal daily dose was 12 g, so patients with a body weight of >80 kg received a dose below 150 mg/kg/day of cloxacillin.
Plasma samples were collected before infusion (t0) and on day 3 of each type of administration. During ItI, total plasma cloxacillin concentrations were obtained 1, 2, 3, 4, and 6 h after the infusion began. During CI, total plasma cloxacillin concentrations were obtained 1, 6, and 11 h after the infusion began. Cloxacillin and deuterated-oxacillin (oxacillin-D5) were purchased from Sigma-Aldrich (catalog no. 27755) and Alsachim (catalog no. C6333), respectively. Cloxacillin plasma concentrations were determined using high-pressure liquid chromatography-tandem mass spectrometry 8040 (Shimadzu Corp., Kyoto, Japan). The analytes were detected using positive ESI mode with selected reaction monitoring with the transition 436.0/160.0 for cloxacillin and 407.1/160.0 for oxacillin-D5. The intraday and interday accuracies in the determination of cloxacillin were, respectively, 2.4 and 7.6% for 13 ng/ml, 1.8 and 6.2% for 62 ng/ml, and 1.2 and 5.8% for 125 ng/ml. The limit of quantification was 0.1 ng/ml (S/N ratio > 10; accuracy, 5.6% [n = 10]). Standard curves were linear and correlation coefficients (r2) were ≥0.998 for concentration ranges of 0.1 to 200 ng/ml. Samples were prepared by adding 200 μl of IS (5 ng/ml in methanol) to 50 μl of plasma. Samples were then mixed and centrifuged for protein precipitation, and the resulting supernatant was gently removed and used for analysis. Both methods were validated according to the French Accreditation Committee and European Medicines Agency guidelines.
Population PK analysis.
Population analysis of PK data were performed by using the R package Pmetrics package. We used the nonparametric algorithm NPAG to estimate population PK parameters (16). One- and two-compartment models, as well as various residual error model, were tested. In covariate modeling, we examined the influence of available covariates on total body clearance and the central volume of distribution. The covariates examined were age, sex, actual body weight, ideal body weight, lean body weight, BSA, treatment sequence (continuous infusion followed by intermittent infusion or vice versa), estimated glomerular filtration rate (CKD-EPI equation), and creatinine clearance (Cockcroft-Gault equation). Both linear and power functions were evaluated in covariate modeling.
Classical criteria were used to evaluate goodness-of-fit and model performance, including the objective function and Akaike information criterion, precision of parameter estimates, bias, and imprecision of model-based predictions. Diagnostic plots were also examined, including regression of predicted versus observed cloxacillin concentrations, scatterplots of residuals, and visual predictive checks obtained after 5,000 replications with the final model.
Dosing simulations and probability of target attainment.
Simulations were performed with the final model to identify optimal dosing regimens of cloxacillin. We simulated 2,000 PK profiles for several dosing regimens: ItI regimens with 2,000 or 3,000 mg administered q6h as a 1-, 2-, 3-, and 4-h infusion, as well as 2,000 mg administered q4h as a 1- and 2-h infusion, and a 24-h-continuous infusion of 6,000, 8,000, 10,000, or 12,000 mg. We examined the influence of BSA on the results by simulating the PK profiles obtained for four values of BSA: 1.5, 1.75, 2, and 2.25 m2.
As a PD target, we considered the percentage of time during which free plasma concentrations of cloxacillin exceeded the MIC (fT>MIC). We assumed a protein binding of 95%, i.e., a free fraction of 5% for cloxacillin (17). In accordance with the distribution of cloxacillin MICs reported by EUCAST for Staphylococcus aureus, we examined MIC values ranging from 0.064 to 2 mg/liter, i.e., up to four times the MIC epidemiological cutoff, which is 0.5 mg/liter. We considered two possible PK/PD targets: fT>MIC ≥ 50% (50% fT>MIC) and fT>MIC = 100% (100% fT>MIC). Acceptable probability of target attainment (PTA) was set at 90%.
Supplementary Material
ACKNOWLEDGMENTS
This study was sponsored by the Centre Hospitalier Universitaire de Nice (University Hospital of Nice) for regulatory and ethical submission. We thank the nurses of the ID department of the Centre Hospitalier Universitaire de Nice who took the numerous blood samples.
This study was funded by Astellas Pharma.
We have no conflicts of interest to declare.
P.-M.R., J.C., and T.L. designed the study. M.G., J.C., R.R., T.L., M.C., J.-L.R., D.C., E.D., L.C., and C.T. collected the data. S.G., M.G., F.J., A.G., and J.C. interpreted the data. M.G., S.G., F.J., A.G., and J.C. wrote the manuscript.
Footnotes
Supplemental material is available online only.
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