Pharmacokinetics of Levofloxacin
Pharmacokinetics of Levofloxacin
Study Objective. To assess the pharmacokinetics of levofloxacin during continuous venovenous hemodiafiltration (CVVHDF) and continuous venovenous hemofiltration (CVVH).
Design. Nonrandomized pharmacokinetic evaluation.
Setting. University surgical intensive care unit.
Patients. Six critically ill patients.
Intervention. Five patients received levofloxacin 500 mg/day and one patient received levofloxacin 125 mg/day. All patients received continuous renal replacement therapy: CVVHDF on day 1 and CVVH on day 2, using an acrylonitrile hollow-fiber 0.9-m filter, constant blood flow rate of 90 ml/minute, substitution flow rate of 1 L/hour predilution, and dialysate flow rate of 1 L/hour (CVVHDF).
Measurements and Main Results. Serum, ultrafiltrate, and dialysate concentrations of levofloxacin were determined by high-performance liquid chromatography. Extracorporeal clearance was 26.05 ± 4.66 ml/hour during CVVHDF and 15.71 ± 2.73 ml/hour during CVVH (p<0.05). Elimination half-life was 28.08 ± 4.5 hours and 45.9 ± 17.7 hours, and distribution volume was 1.51 ± 0.52 L/kg and 1.42 ± 0.42 L/kg for CVVHDF and CVVH, respectively. Saturation was 0.76 ± 0.13 for CVVHDF versus a sieving coefficient of 0.77 ± 0.16 for CVVH.
Conclusion. Marked extracorporeal elimination of levofloxacin occurs, requiring a dosage adjustment that can be calculated from the characteristics of CVVH and CVVHDF.
Levofloxacin is the S-(-)-isomer of the racemic fluoroquinolone ofloxacin. It has a wide spectrum of bactericidal activity in vitro against both gram-positive and gram-negative pathogens, including Legionella, Mycoplasma, Chlamydia, and Mycobacteria sp. In addition, the minimum inhibitory concentrations and resistance for anaerobes such as Bacteroides fragilis, Enterococcus faecium, multiresistant staphylococci, and multi-resistant Pseudomonas aeruginosa are reported to be very high. Because of its broad spectrum of activity, levofloxacin is used for empiric treatment of severe infections, including pneumonia and sepsis, in intensive care units.
The pharmacokinetics and pharmacodynamics of levofloxacin in healthy individuals, elderly patients, and patients undergoing hemodialysis and ambulatory peritoneal dialysis are well known. However, data on the pharmacokinetics of levofloxacin during continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodiafiltration (CVVHDF) are scarce. Continuous venovenous hemofiltration and CVVHDF are the most frequently applied therapies for critically ill patients with acute renal failure. Continuous venovenous hemofiltration removes solutes by convective mass transfer only, whereas CVVHDF increases removal by combining diffusive and convective transport.
Pharmacokinetic data for the racemic compound ofloxacin in healthy individuals are similar to those for levofloxacin in terms of volume of distribution, half-life, total and renal clearance, and protein binding. One thus can expect that optical activity will not influence extracorporeal elimination. Accordingly, it may be permissible to refer to ofloxacin data to assess the extrarenal elimination of levofloxacin during renal replacement therapy. The clearance of ofloxacin in renal insufficiency is markedly reduced, requiring a dosage reduction to avoid accumulation of the drug. No supplemental administration of ofloxacin seems to be necessary after a hemodialysis session. One study addressed ofloxacin clearance during intermittent hemodialysis, but it did not investigate continuous renal replacement therapies. The authors emphasized that for patients undergoing hemodialysis, dosage decisions must take into account the type of dialyzer employed (polysulfone membrane vs cellulose acetate membrane).
At first sight, levofloxacin and ofloxacin would seem ideally suited to elimination by CVVH and CVVHDF. The molecular weight of levofloxacin hemihydrate is 370. D, and the compound has a moderate serum protein binding of 24-38% (serum protein binding for ofloxacin is 25%). Total body clearance of levofloxacin is 143-185 ml/minute or 8.5-11.1 L/hour, compared with 12.8 L/hour for ofloxacin. Levofloxacin undergoes limited metabolism, and nearly 80% (70-90% for ofloxacin) is excreted unchanged in the urine. The half-life of levofloxacin is 6-8 hours (5-7 hrs for ofloxacin), but levofloxacin may persist for as long as 3 days in anuric patients. Levofloxacin has a large volume of distribution, ranging from 0.99-1.47 L/kg (mean 1.25 L/kg) due to its extensive tissue distribution, and neither hemodialysis nor continuous ambulatory peritoneal dialysis have been found to be effective in its elimination. In the elderly, distribution volume is lowered by 18% as a result of reduced lean body mass.
According to published theoretical considerations, the sieving coefficient (Si) corresponds to the unbound fraction of the drug, which is approximately 70% for levofloxacin. Corresponding to the Si during CVVH, the saturation (Sa) of the combined dialysis solution and ultrafiltrate has to be used during CVVHDF. On this basis, the total clearance (Cltot) during CVVHDF with a dialysate flow rate (QF) of 1 L/hour and an ultrafiltrate flow rate (QD) of 1 L/hour (which conform to the CVVHDF characteristics of our study) would be as follows:
Since the nonrenal clearance of levofloxacin corresponds to 20% of the total clearance of 10.8 L/hour in healthy individuals, we can assume a nonrenal clearance of 2.16 L/hour. Total clearance during CVVHDF (ClT-CVVHDF) would be:
Total clearance of levofloxacin during CVVHDF therefore would amount to 32-41% of total clearance in healthy individuals (143-185 ml/hr)14 and should not be neglected.
To date, two published studies have addressed the elimination of levofloxacin during continuous renal replacement therapy in critically ill patients. Neither of these studies investigated CVVHDF. One of the studies, performed by researchers in Austria, investigated elimination of levofloxacin after a single dose, using a high-flux polyamide hemofilter. The authors documented an extrarenal clearance of 27.6 ± 8.4 ml/minute, with an ultrafiltration flow rate of 3.24 ± 0.9 L/hour. The other study, performed in Boston, Massachusetts, using an AN69 polyacylonitrile hemofilter, found a mean clearance by hemofiltration of 13-27 ml/minute (mean 21 ml/min) with an ultrafiltration flow rate of 1.3 L/hour. When a published formula is applied to these CVVH characteristics, as shown below, the calculated total clearance of levofloxacin amounts to 51 ml/minute. This value is close to the results reported by the Boston investigators.
Critically ill patients differ markedly from healthy individuals in terms of serum albumin levels, protein binding of drugs, pH of serum, and volume of distribution of drugs. Moreover, patients with liver or kidney failure differ significantly from healthy individuals with regard to the elimination and metabolism of drugs. The CVVH and CVVHDF procedures can be prescribed at various dosages. Both allow a wide variety of blood flow rates, ultrafiltration rates, and dialysate rates. Differences also may exist with regard to membrane surfaces and other materials, as well as predilution and postdilution substitution flow. All of these variables may influence drug elimination. A higher dosage of renal replacement therapy seems to be correlated with a higher survival rate for critically ill patients with acute renal failure. Residual renal function of a patient with acute renal failure may contribute significantly to total body clearance, thus diminishing the relative contribution of CVVH or CVVHDF. Thus, we sought to evaluate the elimination of levofloxacin by CVVH and CVVHDF and to establish whether this elimination should influence the dosage regimen.
Study Objective. To assess the pharmacokinetics of levofloxacin during continuous venovenous hemodiafiltration (CVVHDF) and continuous venovenous hemofiltration (CVVH).
Design. Nonrandomized pharmacokinetic evaluation.
Setting. University surgical intensive care unit.
Patients. Six critically ill patients.
Intervention. Five patients received levofloxacin 500 mg/day and one patient received levofloxacin 125 mg/day. All patients received continuous renal replacement therapy: CVVHDF on day 1 and CVVH on day 2, using an acrylonitrile hollow-fiber 0.9-m filter, constant blood flow rate of 90 ml/minute, substitution flow rate of 1 L/hour predilution, and dialysate flow rate of 1 L/hour (CVVHDF).
Measurements and Main Results. Serum, ultrafiltrate, and dialysate concentrations of levofloxacin were determined by high-performance liquid chromatography. Extracorporeal clearance was 26.05 ± 4.66 ml/hour during CVVHDF and 15.71 ± 2.73 ml/hour during CVVH (p<0.05). Elimination half-life was 28.08 ± 4.5 hours and 45.9 ± 17.7 hours, and distribution volume was 1.51 ± 0.52 L/kg and 1.42 ± 0.42 L/kg for CVVHDF and CVVH, respectively. Saturation was 0.76 ± 0.13 for CVVHDF versus a sieving coefficient of 0.77 ± 0.16 for CVVH.
Conclusion. Marked extracorporeal elimination of levofloxacin occurs, requiring a dosage adjustment that can be calculated from the characteristics of CVVH and CVVHDF.
Levofloxacin is the S-(-)-isomer of the racemic fluoroquinolone ofloxacin. It has a wide spectrum of bactericidal activity in vitro against both gram-positive and gram-negative pathogens, including Legionella, Mycoplasma, Chlamydia, and Mycobacteria sp. In addition, the minimum inhibitory concentrations and resistance for anaerobes such as Bacteroides fragilis, Enterococcus faecium, multiresistant staphylococci, and multi-resistant Pseudomonas aeruginosa are reported to be very high. Because of its broad spectrum of activity, levofloxacin is used for empiric treatment of severe infections, including pneumonia and sepsis, in intensive care units.
The pharmacokinetics and pharmacodynamics of levofloxacin in healthy individuals, elderly patients, and patients undergoing hemodialysis and ambulatory peritoneal dialysis are well known. However, data on the pharmacokinetics of levofloxacin during continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodiafiltration (CVVHDF) are scarce. Continuous venovenous hemofiltration and CVVHDF are the most frequently applied therapies for critically ill patients with acute renal failure. Continuous venovenous hemofiltration removes solutes by convective mass transfer only, whereas CVVHDF increases removal by combining diffusive and convective transport.
Pharmacokinetic data for the racemic compound ofloxacin in healthy individuals are similar to those for levofloxacin in terms of volume of distribution, half-life, total and renal clearance, and protein binding. One thus can expect that optical activity will not influence extracorporeal elimination. Accordingly, it may be permissible to refer to ofloxacin data to assess the extrarenal elimination of levofloxacin during renal replacement therapy. The clearance of ofloxacin in renal insufficiency is markedly reduced, requiring a dosage reduction to avoid accumulation of the drug. No supplemental administration of ofloxacin seems to be necessary after a hemodialysis session. One study addressed ofloxacin clearance during intermittent hemodialysis, but it did not investigate continuous renal replacement therapies. The authors emphasized that for patients undergoing hemodialysis, dosage decisions must take into account the type of dialyzer employed (polysulfone membrane vs cellulose acetate membrane).
At first sight, levofloxacin and ofloxacin would seem ideally suited to elimination by CVVH and CVVHDF. The molecular weight of levofloxacin hemihydrate is 370. D, and the compound has a moderate serum protein binding of 24-38% (serum protein binding for ofloxacin is 25%). Total body clearance of levofloxacin is 143-185 ml/minute or 8.5-11.1 L/hour, compared with 12.8 L/hour for ofloxacin. Levofloxacin undergoes limited metabolism, and nearly 80% (70-90% for ofloxacin) is excreted unchanged in the urine. The half-life of levofloxacin is 6-8 hours (5-7 hrs for ofloxacin), but levofloxacin may persist for as long as 3 days in anuric patients. Levofloxacin has a large volume of distribution, ranging from 0.99-1.47 L/kg (mean 1.25 L/kg) due to its extensive tissue distribution, and neither hemodialysis nor continuous ambulatory peritoneal dialysis have been found to be effective in its elimination. In the elderly, distribution volume is lowered by 18% as a result of reduced lean body mass.
According to published theoretical considerations, the sieving coefficient (Si) corresponds to the unbound fraction of the drug, which is approximately 70% for levofloxacin. Corresponding to the Si during CVVH, the saturation (Sa) of the combined dialysis solution and ultrafiltrate has to be used during CVVHDF. On this basis, the total clearance (Cltot) during CVVHDF with a dialysate flow rate (QF) of 1 L/hour and an ultrafiltrate flow rate (QD) of 1 L/hour (which conform to the CVVHDF characteristics of our study) would be as follows:
| Cltot = Clnonrenal + ClCVVHDF | |
| ClCVVHDF | = (QF + QD) Sa = 2 L/hour 0.70 |
| = 1.4 L/hour | |
Since the nonrenal clearance of levofloxacin corresponds to 20% of the total clearance of 10.8 L/hour in healthy individuals, we can assume a nonrenal clearance of 2.16 L/hour. Total clearance during CVVHDF (ClT-CVVHDF) would be:
| ClT-CVVHDF | = 2.16 L/hour + 1.4 L/hour |
| = 3.56 L/hr (or 59.3 ml/min) |
Total clearance of levofloxacin during CVVHDF therefore would amount to 32-41% of total clearance in healthy individuals (143-185 ml/hr)14 and should not be neglected.
To date, two published studies have addressed the elimination of levofloxacin during continuous renal replacement therapy in critically ill patients. Neither of these studies investigated CVVHDF. One of the studies, performed by researchers in Austria, investigated elimination of levofloxacin after a single dose, using a high-flux polyamide hemofilter. The authors documented an extrarenal clearance of 27.6 ± 8.4 ml/minute, with an ultrafiltration flow rate of 3.24 ± 0.9 L/hour. The other study, performed in Boston, Massachusetts, using an AN69 polyacylonitrile hemofilter, found a mean clearance by hemofiltration of 13-27 ml/minute (mean 21 ml/min) with an ultrafiltration flow rate of 1.3 L/hour. When a published formula is applied to these CVVH characteristics, as shown below, the calculated total clearance of levofloxacin amounts to 51 ml/minute. This value is close to the results reported by the Boston investigators.
| ClCVVH = 1.3 L/hour 0.7 = 0.9 L/hour | |
| Cltot | = Clnonrenal + ClCVVH = 0.9 L/hour + 2.16 L/hour |
| = 3.06 L/hour (or 51 ml/min) | |
Critically ill patients differ markedly from healthy individuals in terms of serum albumin levels, protein binding of drugs, pH of serum, and volume of distribution of drugs. Moreover, patients with liver or kidney failure differ significantly from healthy individuals with regard to the elimination and metabolism of drugs. The CVVH and CVVHDF procedures can be prescribed at various dosages. Both allow a wide variety of blood flow rates, ultrafiltration rates, and dialysate rates. Differences also may exist with regard to membrane surfaces and other materials, as well as predilution and postdilution substitution flow. All of these variables may influence drug elimination. A higher dosage of renal replacement therapy seems to be correlated with a higher survival rate for critically ill patients with acute renal failure. Residual renal function of a patient with acute renal failure may contribute significantly to total body clearance, thus diminishing the relative contribution of CVVH or CVVHDF. Thus, we sought to evaluate the elimination of levofloxacin by CVVH and CVVHDF and to establish whether this elimination should influence the dosage regimen.