Pharmacokinetics and the optimal regimen for levofloxacin in critically ill patients receiving continuous hemodiafiltration
© Wada et al.; licensee BioMed Central. 2015
Received: 10 January 2015
Accepted: 23 April 2015
Published: 8 May 2015
The aim of this study was to establish the pharmacokinetics of levofloxacin (LVFX) and determine the optimal dose of this drug in critically ill patients receiving continuous hemodiafiltration (CHDF). The results of in vivo and in vitro studies showed the pharmacokinetics of LVFX total clearance (CLtotal) according to the creatinine clearance (CLCre), dialysate flow (QD), and ultrafiltrate flow (QF), to be as follows: CLtotal (l/h) = 0.0836 × CLCre (ml/min) + 0.013 × body weight (kg) + 0.94(QD + QF) (l/h). The optimal dose of LVFX was expressed by the following formula: 50 × CLtotal. These results demonstrate that the usual dose of LVFX (500 mg) was sufficient for the patients evaluated in this study.
KeywordsLevofloxacin Pharmacokinetics Continuous hemodiafiltration Clearance
Critically ill patients often require continuous hemodiafiltration (CHDF) as a result of acute kidney injury induced by severe sepsis. Levofloxacin (LVFX) is widely used for treatment in these patients. However, the pharmacokinetics (PK) of LVFX during CHDF are not uniform, as CHDF is performed using various combinations of the dialysate flow (QD) and ultrafiltrate flow (QF). The aim of the present study was to estimate the PK of LVFX in patients receiving CHDF and determine the optimal dose of LVFX for this patient population.
Approval for this study was obtained from the institutional review board, − The Ethics Committee of Hokkaido University School of Medicine (011–0107). Informed consent for this study was obtained from the patients’ next of kin.
In vitro study
A CHDF circuit model (JUN-600, JUN-KEN MEDICAL Co., Tokyo, Japan) was established using a cellulose triacetate hollow fiber 1.1 m2 hemofilter (UT-1100, Nipro, Japan). The machine was primed with fresh frozen plasma (FFP), and 100 mg of LVFX were added to the circuit. The FFP flow was fixed at 150 ml/min, and the CHDF conditions were as follows: the QD was defined from 0, 1, and 2 l/h; the QF was defined from 0, 1, and 2 l/h, independent of QD. Samples were obtained from the prehemofilter and ultrafiltrates at 15, 30, 45, and 60 min after the start of CHDF. The sieving coefficient (SC) values were calculated based on the LVFX concentrations in the filtrates and prehemofilter. The levels of clearance (CL) via CHDF (CLCHDF) were obtained for the product of SC and (QD + QF) and then were plotted, respectively.
In vivo study
Characteristics of the patients
The cause of AKI
The value of Cre on admission to ICU (mg/dl)
Duration of CHDF (days)
Congenital heart disease
Major cardiac operation
Mean ± SE
59.5 ± 6.0
70.0 ± 8.5
33.8 ± 4.9
1.25 + 0.29
38.5 + 12.7
24 h CL cre (ml/min)
Q D (l/h)
Q F (l/h)
Predictive CL total (l/h)
Calculated optimal dose of LVFX (mg)
39.3 ± 5.0
2.6 ± 0.8
0.86 + 0.13
1.88 + 0.13
3.6 ± 0.4
182 + 18.3
Pharmacokinetic parameters of levofloxacin in the patients receiving continuous hemodiafiltration
CL total (l/h)
t 1/2 (h)
C max (mcg/ml)
AUC [(mg/l) h]
Mean ± SE
7.63 + 1.6
16.9 + 4.0
4.5 + 0.6
73.9 + 13.8
The ratio of AUC/minimum inhibitory concentration (MIC) is a well-known important PK and pharmacodynamics predictor of the clinical efficacy of fluoroquinolones, including LVFX. Previous studies suggest that the AUC/MIC of ≥100 (h) is required in compromised patients or those exhibiting severe Gram-negative rod or staphylococcal infection [2-4]. In addition, the MIC for 90% of tested strains against most common Gram-negative aerobic pathogens is < 0.5 (μg/ml) . Therefore, we determined the target AUC to be ≥ 50 and the optimal dose of LVFX to be 50 × CLtotal. Hence, the LVFX concentrations reached higher than optimal concentrations, and infection could therefore be successfully controlled in these patients.
Three factors affect the PK during CHDF as follows: 1) pore size and protein binding fraction of the drug; 2) molecular size; 3) QD and QF in the CHDF protocol . The triacetate and polysulfone membranes used in this study have large pores and do not have a capacity for drug absorption, characteristics recommended for CHDF. The molecular size of LVFX is 361 Da, which is less than that of ciprofloxacin (CPFX) (368 Da). The results of our previous study suggested that the pore size of the hemofilter does not influence the CLCHDF, likely due to the sufficiently low molecular weight of CPFX . This previous study also indicated that the surface area of the hemofilter with a large amount of QD possibly affects the clearance of small solutes, such as fluoroquinolones . Therefore, the current results are not applicable in cases in which the QD is large.
The limitations of this study should be addressed. First, the results of a study by Takigawara et al. , showing the relationship between the PK of LVFX and the CLCre, were based on patients with a normal renal function. These results are not applicable to the present study, as we included patients with more severe kidney injury. Second, the current study included a very small number of patients. Therefore, a larger, more precise clinical study is needed to confirm our results.
- CLCre :
- QD :
- QF :
- CLtotal :
LVFX total clearance
fresh frozen plasma
- CLCHDF :
clearance by CHDF
- CL vivo :
clearance in patients
area under the concentration-time curve
minimum inhibitory concentration
This study was supported by a Grant-in-Aid for Young Scientists (B) (2013–25861736) from the Ministry of Education, Science, Sports and Culture of Japan.
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