Pharmacokinetics and pharmacodynamics of Linezolid in burn patients

Summary

Burns induce complex physiological changes such as modification of distribution volume, increased clearance of elements and decrease of protein binding. The pharmacokinetics of many antibiotics may then be modified, which requires dose adjustment. We attempted to evaluate the pharmacokinetics of linezolid in burn patients at a standard dose of 600 mg intravenously thrice a day. A prospective study was conducted in a 20-bed adult burn ICU at a university-affiliated teaching hospital in Tunis. Thirteen adult burned patients with documented and/or suspected multi drug resistant (MDR) gram-positive bacterium-related infections were enrolled in the study. Our study suggests that linezolid dosing at 600mg thrice a day leads to adequate pharmacodynamic/pharmacokinetic exposure to linezolid with a Cmin > 2mg/l in 84.6% of cases, T > MIC in about 87.5% and AUC/MIC > 100 in 61.5% of cases. However, a high variability in linezolid serum concentrations with a substantial percentage of sub-therapeutic levels was observed in a few patients, 15% of cases. Therefore, therapeutic drug monitoring of linezolid might be helpful for adequate dosing of linezolid in burned patients, to avoid the risk of treatment failure or of dose-dependent toxicity.

Introduction

Sub-therapeutic concentrations of antimicrobial treatment lead to antibioresistance, which threatens the management of bacterial infections in critically ill patients1 and is associated with high morbidity-mortality. In addition, the escalating problem of antimicrobial resistance has substantially increased overall health care costs as a result of prolonged hospitalizations and convalescence associated with antibiotic treatment failures, the need to develop new antimicrobial agents, and the implementation of broader infection control and public health interventions aimed at reducing the spread of antibiotic-resistant pathogens.

Patients with major burns experience pathological changes that have been shown to influence the pharmacokinetics of antibiotics. Subsequently, it has been demonstrated that conventional doses of some antibiotics given to patients with major burns may result in sub-therapeutic serum concentrations. The linezolid -oxazolidinone- is one of the new agents approved for the treatment of infections caused by multidrug-resistant gram-positive bacteria^2,3,4 that are common in burn patients. Therefore, therapeutic drug monitoring (TDM) of linezolid could be especially helpful for dosage adjustment in these patients. Significant underexposure with increased risk of therapeutic failure was documented in patients with major thermal injuries.^5,6 In the literature, there is little data on the pharmaco-kinetics of linezolid in burn patients. Lauren et al.⁵ have demonstrated that if linezolid is used in thermal patients as a 600 mg intravenous dose twice a day, blood concentrations may be relatively low and the risk of emergence of resistance to linezolid is increased, indicating that higher doses will be needed. Consequently, this study was undertaken to evaluate the pharmacokinetics of linezolid in burn patients at 600mg/8h, to identify the prevalence of optimal pharmacodynamic exposure enabled by the dosing regimen according to the pharmacokinetic/ pharmacodynamic principles and to the pattern of susceptibility to this antibiotic.

Patients and methods

A prospective study approved by our institution’s Ethics Committee was conducted in a 20-bed adult burn ICU at a university-affiliated teaching hospital in Tunis. Informed consent was obtained from all participants or next of kin. Participation did not modify the therapeutic strategy. Adult burn patients admitted to the ICU burn unit, suffering from burns greater than 20% TBSA, and those with documented and/or suspected multi drug resistant (MDR) gram-positive bacterium-related infections from March 1st to May 31st, 2014 were included in the study. Any patients with infections prior to the burn injury, or those who were discharged or died within 48h after admission were ruled out of the study. Pregnant women, patients aged under 18 years old and those who received an antidepressant treatment type inhibitor of serotonin recapture (IRSS) were excluded. Consent was obtained from the patient or their legal representative.

After inclusion, enrolled patients received 600 mg of linezolid administered in 1-hour infusions three times per day. Blood samples for pharmacokinetic analysis were taken immediately, 5 min after the end of the first infusion (t1), 5 min before the second (t2) and the third dose (t3) and finally 5 min before the dose of the day after (t4). To assess linezolid serum level, 4 mL of blood was drawn from an arterial line, centrifuged and then stored at -80°C. Linezolid minimum inhibitory concentrations (MIC) were 4μg/dL. The pharmacokinetic (PK) characteristics of linezolid include approximately 100% bioavailability and a relatively low level of plasma protein binding (approximately 30%).⁶ Thresholds for therapeutic efficacy of linezolid were defined as: Cmin > 2 mg/L and/or AUC24 > 200 mgh/L or when linezolid exceeds the minimum inhibitory concentration (MIC) over the entire dosing interval or when AUC24/MIC values are higher than 80 to 120, with clinical cure and bacterial eradication endpoints. ^7,8 The threshold for potential therapeutic toxicity was defined as trough levels >10 mg/L or AUC24 values > 400 mg*h/L according to the literature.^9-11

For all patients, linezolid minimum inhibitory concentration (MIC), and linezolid plasma concentrations (trough (Cmin) and peak (Cmax) levels) were analysed. Also, the AUC0_24h (daily area under the plasma concentration–time curve) was calculated using the linear trapezoidal rule and also T > MIC percentage of dosing interval during which antibiotic concentration remained above the MIC of targeted bacteria. Exploitation of data was performed using SPSS 21.0. For statistical analysis, we used the Chi-2 test or Fisher test when the conditions of validity of the Chi-2 test were not met. A value of p ≤ 0.05 was considered statistically significant for the comparison of results. The different predictive values were studied with the area under the ROC curve. Optimum sensitivity, predictive value and area under the receiver operating characteristic (ROC) curve were evaluated.

Results

Septic patients with documented and/or suspected multi drug resistant (MDR) gram-positive bacterium-related infections were considered eligible for enrolment in the study. Predictive signs of sepsis were defined according to the Society of Critical Care Medicine/European Society of Intensive Care Medicine (SCCM/ESICM) Consensus Conference Committee.¹²

Enrolled patients (n=13) received linezolid as a 30 min intravenous administration at a dosing of 600mg/8H. Clinical patient data were recorded. Response to treatment was favourable if there was resolution of signs and symptoms at inclusion, and considered a failure if symptoms persisted, new signs of infection presented and/or there was organ failure. Patients were treated for sepsis according to published guidelines (sepsis campaign). Microbiological samples were drawn from blood or any other suspected site of infection before the first dose of linezolid. A total of 226 patients were admitted to our burn unit during the period of the study. Thirteen burned patients were included in the study: 9 males and 4 females with a mean age of 37±20 years (range: 17 to 79 years). The mean weight at admission was 65±7 kg. The mean burned area was 30±10% (16 to 43%). No case of renal function or of thrombocytopenia was noted in any of the patients, with respectively creatinine concentrations of 90μmol/l and a mean platelet count of 268.000 el/mm.³

Linezolid serum Cmax after the first dose was 21 mg/L. The mean serum concentration at 5 min before the second and the third dose was respectively 4.88 mg/L and 5.33 mg/l. At 5 min before the dose of the day after the mean serum concentration was 5.51 mg/l.

Mean plasma concentrations of linezolid in all patients are shown in Fig. 1.

Fig. 1. Mean plasma concentrations of linezolid in all patients.

Optimal pharmacodynamic exposure over 24 h with AUC24 values between 200 and 400 mg*h/L and with Cmin values between 2 and 10 mg/L was observed in 38% and 85% of the patients, respectively. Regarding linezolid pharmacokinetic parameters for each patient, we noted a high inter-patient variability: AUC24 values ranged from 107.49 to 488.94 mg/h/L (median 234.8 mg/h/L), and there was also a high inter-patient variability for single Cmin values (range from 0.75 to 8.31 mg/L, median 4.12 ± 2.46 mg/L) (Table I).

Table I. Linezolid pharmacokinetic parameters of all patients.

Moreover, regarding these AUC24 and Cmin values, 54% and 15% of the study patients had linezolid concentrations below the lower limit of the corresponding target concentration range, respectively, and only one patient had linezolid concentrations above the target concentration range. To demonstrate the usefulness of Cmin values for TDM of linezolid, Cmin values were correlated with corresponding AUC24 values giving an r2 value of 0.77. For the PK/PD analysis, the T > MIC (T= time with serum concentrations higher than the MIC) and the AUC/MIC were calculated for each patient. The median T > MIC was 87.5% and the median AUC/MIC was 117.39 mg/L. The T > MIC was higher than 85% (Fig. 2) and the AUC/MIC > 100 in 61.5% of cases (Tables I and II).

Fig 2. Linezolid pharmacokinetic parameters of all patients.

Table II. T > MIC of all patients.

Discussion

Our results suggest that linezolid exposure in our patients after standard dosing of 600 mg intravenously thrice a day leads to optimal pharmacodynamic exposure over 24 h with a median AUC24 at 234.8 mg/h/L in 38% and a median Cmin value at 4.12 ± 2.46 mg/L in 85% of the patients, respectively. Furthermore, a high variability in linezolid levels was observed in the study population. However, regarding results published in the literature, Lovering et al. reported that the pharmacokinetics of linezolid are altered with sub-therapeutic concentrations in major thermal injured patients receiving linezolid at a single dose of 600mg once daily compared to healthy volunteers matched by sex, age and weight.¹³ Also, low AUC24 or Cmin values with the majority being insufficient were reported in adult patients with suspected infections who received standard dosing of 600 mg linezolid intravenously twice a day.^14-16 Therefore, we can suggest that major burned patients required linezolid at a dosing of 600 mg thrice a day to achieve threshold therapeutic efficacy.

In the literature, Rayner et al. showed in a large compassionate- use study that the PK/PD analysis of linezolid correlated AUC/MIC and %TMIC values of 100 and 85, respectively, with clinical cure and bacterial eradication end points.¹⁷ In our series, 61.5% of patients reached these target concentration ranges. So, optimisation of linezolid use through the integration of PK/PD parameters is essential to avoid emerging resistance to antimicrobials.¹⁸ Also, Zoller et al.¹⁴ demonstrated in a prospective observational study including 30 critically ill adult patients with suspected infections receiving standard dosing of 600 mg linezolid intravenously twice a day, that Cmin values were correlated with corresponding AUC24 values, giving an r2 value of 0.79. This result was in concordance with our results, showing that for our patients Cmin values were correlated with corresponding AUC24 values, giving an r2 value of 0.77. So, the good linear relationship between Cmin and estimated AUC24 suggests that Cmin may be useful for TDM linezolid in clinical practice. In our series, Cmin> 2mg/l was noted in 84.6% of cases. Also, therapeutic drug monitoring of Cmin could be used to guide dosage adjustment with linezolid in individual patients with the intent of avoiding either the risk of toxicity or that of therapeutic failure. In fact, in the literature authors demonstrated that decreased susceptibility to linezolid (4-fold increases in MIC) during treatment also exhibited AUC/MIC and %TMIC values <100, suggesting an influence of PK/PD in linezolid resistance development. ¹⁰

Conclusion

Our study suggests that in burn patients the standard dosing of 600-mg thrice a day leads to adequate pharmacodynamic/ pharmacokinetic exposure to linezolid with a Cmin>2mg/l in 84.6% of cases, T > MIC in about 87.5% and AUC/MIC > 100 in 61.5% of cases. However, a high variability of linezolid serum concentrations with a substantial percentage of sub-therapeutic levels was observed in a few patients. The findings suggest that therapeutic drug monitoring of linezolid might be helpful for adequate dosing of linezolid in burned patients to avoid the risk of treatment failure or of dose-dependent toxicity. Therefore, future prospective studies with large samples should focus on assessing the clinical relevance of the correlation between linezolid TDM and efficacy or toxicity, and as a consequence, infection-related patient outcome.