Levofloxacin Pharmacokinetics and Pharmacodynamics in Patients with Severe Burn Injury

Abstract

Levofloxacin pharmacokinetics were studied in 11 patients with severe burn injuries. Patients (values are means ؎ standard deviations; age, 41 ؎ 17 years; weight, 81 ؎ 12 kg; creatinine clearance, 114 ؎ 40 ml/min) received intravenous levofloxacin at 750 mg (n ‫؍‬ 10 patients) or 500 mg (n ‫؍‬ one patient) once daily. Blood samples were collected on day 1 of levofloxacin therapy; eight patients were studied again on days 4 to 6. The pharmacodynamic probability of target attainment (PTA) was evaluated by Monte Carlo simulation. Mean systemic clearance, half-life, and area under the concentration-time curve over 24 h after levofloxacin at 750 mg were 9.0 ؎ 3.2 liters/h, 7.8 ؎ 1.6 h, and 93 ؎ 31 mg · h/liter, respectively. There were no differences in pharmacokinetic parameters between day 1 and day 4; however, large intrapatient and interpatient variability was observed. Levofloxacin pharmacokinetics in burned patients were similar to those reported in other critically ill populations. Levofloxacin at 750 mg achieved >90% PTA for gram-negative and gram-positive pathogens with MICs of <0.5 g/ml and MICs of <1 g/ml, respectively. However, satisfactory PTA was not obtained with less-susceptible gram-negative organisms with MICs of 1 g/ml or any organism with a MIC of >2 g/ml. The results of this study indicate that levofloxacin should be administered at 750 mg/day for treatment of systemic infections in severely burned patients. However, even 750 mg/day may be inadequate for gram-negative organisms with MICs of 1 to 2 g/ml even though they are defined as susceptible. Alternative antibiotics or treatment strategies should be considered for infections due to these pathogens.

In silico trials using Monte Carlo simulation to evaluate ciprofloxacin and levofloxacin dosing in critically ill patients receiving prolonged intermittent renal replacement therapy

“…However, in this case, it would appear to be unethical to conduct a fluoroquinolone PIRRT pharmacokinetic trial with the doses that achieved 90 % PTA because these doses are likely to be toxic. We have confidence that the model performed accurately based on the fact that our findings independently corroborate reports that conventionally dosed fluoroquinolones rarely achieve therapeutic targets in critically ill patients, and like those reports [36,[45][46][47][48][49], we also do not recommend their use as empiric monotherapy in this population receiving PIRRT due to the concern for suboptimal serum concentration attainment that contributes to increasing bacterial resistance. Although smaller levofloxacin doses can be used to treat S. pneumonia in PIRRT patients based on our data, the maximal FDA-approved fluoroquinolone dose should be used as empiric treatment for infected critically ill patients with PIRRT as combination therapy when necessary.…”

“…For levofloxacin, 2000 mg was required for day 1 and 1000 mg on days 2 and 3. These MCS results are not surprising, because of the growing realization that conventional fluoroquinolone doses do not reliably achieve the pharmacodynamic target of AUC 24h :MIC ≥125 in infected critically ill patients with or without RRT [36,[45][46][47][48][49]. In a recent report, ciprofloxacin 1600 mg/day was necessary to attain AUC 24h :MIC ≥125 (bacterial susceptibility of MIC ≤ 1 mg/L) at a steady state in an obese critically ill patient receiving CRRT [49].…”

Pharmacokinetics and pharmacodynamics of levofloxacin in critically ill patients with ventilator-associated pneumonia

“…three-fold higher for the optimum AUC than is achievable with the present dosing regimen in critically ill patients with normal renal function. As at the highest dose (1000 mg/day) that could be safely administered [38], only bacteria with an MIC of ≤1.5 mg/L could be treated successfully, there is a potential risk of levofloxacin therapy failure in cases when the bacterium is labelled as being sensitive (MIC ≤ 2 mg/L) in the bacteriological report [6,39,40]. Thus, lowering the MIC breakpoint for levofloxacin is proposed.…”

Effect of Differences in MIC Values on Clinical Outcomes in Patients with Bloodstream Infections Caused by Gram-Negative Organisms Treated with Levofloxacin

“…One study using these techniques compared the CLSI MIC breakpoints to achievable PK profiles and showed that fluoroquinolone breakpoints derived from PK-PD theory for aerobic gram-negative bacteria were lower than current CLSI susceptibility breakpoints (18). Another recent study by Kiser and colleagues evaluated levofloxacin PKs-PDs in severe burn injury (21). Using a Monte Carlo simulation, they showed that for patients infected with gram-negative organisms for which MICs were Յ0.5 g/ml, the probability of achieving an AUC 0-24 /MIC ratio of Ն87 was 100%, but for patients infected with organisms for which MICs were 1 or 2 g/ml, which are classified as susceptible by CLSI standards, the probability was 55 or 0%, respectively.…”