Special Feature

Linezolid Dosing in Special Populations

By Jessica C. Song, MA, PharmD, Assistant Professor, Pharmacy Practice, University of the Pacific, Stockton, CA; Pharmacy Clerkship and Coordinator, Santa Clara Valley Medical Center, is Associate Editor for Infectious Disease Alert.

Dr. Song reports no financial relationship to this field of study.

Linezolid is an oxazolidinone agent that has been shown to be effective for the treatment of infections caused by Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE).1 Linezolid exhibits linear pharmacokinetics, since the area under the plasma concentration-time curve (AUC) increases with dosing increments. In addition, this drug displays time-dependent antibacterial activity, since bacterial killing is correlated with the time during which the plasma drug concentration remains above the minimum inhibitory concentration (MIC), along with the ratio between AUC and the MIC (AUC/MIC). Optimal bacterial killing has been shown to occur with an AUC/MIC in excess of 100, along with a T > MIC of 100%.1

Linezolid is a moderately lipophilic drug and it primarily undergoes nonrenal clearance (65%). The remaining 35% of the total dose of linezolid appears unchanged in the urine.2 At present, therapeutic drug monitoring (TDM) of linezolid has not been adopted by institutions worldwide, but may be warranted in some settings. Pea and associates recently reported on their experiences of linezolid TDM at the Institute of Clinical Pharmacology and Toxicology (University of Udine).2 Findings from this retrospective review were indicative of potential underexposure in 28% of cases.

The purpose of this review is to discuss appropriate dosing of linezolid in renally impaired patients, liver transplant recipients, cystic fibrosis patients, and burn patients.

Linezolid Dosing in Patients with Renal Impairment

Renal excretion of linezolid does not appear to be affected by decreases in creatinine clearance, provided that the creatinine clearance remains above 10 mL/min.2 However, definitive evidence is lacking for dosing recommendations in end stage renal disease (ESRD) patients and in patients requiring continuous renal replacement therapy.

Tsuji et al studied the association of the occurrence of adverse hematologic effects with blood linezolid concentration and AUC0-24 in renally impaired patients who received this agent for MRSA infection.3 Three cases of linezolid-associated thrombocytopenia were highlighted; the three patients received intravenous linezolid 600 mg dosed every 12 hours for 13-16 days. The patients' estimated glomerular filtration rates (GFR) ranged from 12 mL/min to 39 mL/min. Blood samples were taken from the three patients at 20 time points. Tsuji and associates reported a strong negative correlation between AUC0-24 and hemoglobin level (r = 0.783; P < 0.01), whereas the correlation between AUC0-24 and platelet count was shown to be weak (r = 0.593; P < 0.01).

Pea and associates examined the effect of continuous venovenous hemofiltration (CVVH) on the pharmacokinetic profile of linezolid in two patients with severe, postsurgical, intra-abdominal infections.4 The two patients received pump-driven CVVH (Aquarius, Edwards Lifesciences, Unterschleibheim, Germany), set at a flow rate of 120-130 mL/min, and with a substitution rate of 2000 mL/h. The polysulfone Aquamax PSHF 1200-based hemofilter has an effective surface area of 1.25 m2. Patient 1 had blood samples taken on day 28 of therapy, with blood draws done 1 hour before dosing and at 0, 0.5, 1, 2, 3, 5, 7, 9, and 11 hours after the morning intravenous infusion of linezolid 600 mg. Patient 2 underwent 10 blood draws (same times as patient 1) on day 4 of therapy.

Patients 1 and 2 exhibited similar hemofiltration clearances (ClCVVH; 0.38 vs. 0.35 mL/min/kg), but Patient 1 showed a higher proportion of clearance through hemofiltration (69% of total linezolid clearance) than patient 2 (29% of total linezolid clearance). Patients 1 and 2 eliminated 314 mg and 160 mg of linezolid, respectively, through hemofiltration during the dosing interval. Linezolid plasma trough concentrations were 21.7 mg/L and 6.5 mg/L for patients 1 and 2, respectively. Both patients had AUC/MIC ratios greater than 100 hours and neither patient required drug withdrawal for linezolid-related toxicity. Pea and associates proposed that the high drug exposure of Patient 1 could have resulted from nonlinear elimination arising from saturation of one of the two major metabolic pathways.

Linezolid Dosing in Liver Transplant Recipients

There are scant data for the dosing of linezolid in hepatically impaired patients. Pea and associates reported on a case of hyperlactacidemia associated with linezolid therapy in a 59-year-old liver transplant recipient who developed bilateral pneumonia 4 days post-surgery.5 On day 10 of linezolid therapy, multiple blood samples were obtained in order to conduct a pharmacokinetic analysis of linezolid exposure in this patient, since an asymptomatic rise in plasma lactate levels had been noted (peak level, 8.4 mmol/L) since day 4 of linezolid therapy. The pharmacokinetic analysis revealed an AUC0-12 of 412.55 mg × h/L, a maximum concentration of 43.32 mg/L, a trough concentration of 26.99 mg/L, and an elimination half-life of 16.57 hours, clearly indicating plasma overexposure to linezolid.

Within 48 hours of discontinuing linezolid therapy, lactate levels normalized in this patient. The authors stated the possibility that linezolid-associated hyperlactacidemia could be caused by inhibition of mitochondrial protein synthesis, but that the true mechanism of linezolid overexposure had yet to be elucidated. Of note, the patient described in this report received sertraline during linezolid therapy. The authors proposed that linezolid clearance could have been impaired by blockade of p-glycoprotein activity by sertraline.

Linezolid Dosing in Cystic Fibrosis Patients

Cystic fibrosis patients often develop serious and potentially life-threatening respiratory tract infections, so the study of linezolid pharmacokinetics in this population merits particular attention. Bosso and associates conducted a study of 12 cystic fibrosis patients, whose ages ranged from 22 to 39 years.6 Blood draws occurred immediately before drug infusion and at 0.5, 0.75, 1, 2, 4, 8, and 24 hours after drug infusion. The pharmacokinetic analysis revealed a wide degree of variability in the pharmacokinetic parameters of linezolid observed in the 12 subjects, and the extremes of the pharmacokinetic values were within ranges previously reported for healthy adults. However, when the authors assumed a theoretical value of 4 mg/L for the MIC, none of the subjects achieved AUC0-∞/MIC ratios of > 80 hours; observed AUC0-∞/MIC ranged from 16.30 to 52.24 hours.

Linezolid Dosing in Burn Patients

Patients with burn injuries display numerous physiologic alterations affecting organ function and drug metabolism.7 Patients experiencing large burns may exhibit increased drug volumes of distribution due to changes in fluid volumes of key body compartments, thereby decreasing the concentration when a standard dose is administered. In addition, higher drug clearance and shorter elimination half-lives may be observed in burn patients, due to increased renal blood flow secondary to changes in cardiac output.7

Hallam et al reported on the case of a 27-year-old male burn patient (52% body surface area affected) who required an increase in the dosing frequency of linezolid for lobar pneumonia.7 On hospital day 12, the patient started intravenous linezolid (600 mg twice daily), following a 7-day course of piperacillin-tazobactam and 4 days of meropenem therapy. After 48 hours of linezolid therapy, pharmacokinetic analysis revealed a percentage of dose interval above 4 mg/L of 20% for linezolid (600 mg twice daily). Consequently, the dosing interval was shortened from 12 hours to 8 hours on hospital day 15. The patient became afebrile and his white count decreased from 36 × 109/L to 13.6 × 109/L on day 16. Moreover, the percentage of dose interval above 4 mg/L increased to 70% with the every 8-hour dosing regimen. Antibiotic therapy was discontinued on hospital day 19.

Conclusion

The standard regimen of linezolid (600 mg twice daily) does not require modification in the majority of patients, including patients with mild renal and hepatic impairment. However, certain patient populations have been shown to achieve insufficient AUC/MIC or T > MIC values, thereby increasing the risk for the development of resistant strains.2 Conversely, other patient populations with overexposure to linezolid could be at risk for severe toxic effects against target organs (brain, optic nerve, kidney, skeletal muscular tissue).2 TDM might be warranted in patients with significant burn injuries, in patients with cystic fibrosis or ESRD, and in patients undergoing renal replacement treatment.

References

  1. Di Paolo A, et al. Pharmacological issues of linezolid: An updated critical review. Clin Pharmacokinet 2010;49:439-447.
  2. Pea F, et al. Therapeutic drug monitoring of linezolid: A retrospective monocentric analysis. Antimicrob Agents Chemother 2010;54:4605-4610.
  3. Tsuji Y, et al. Thrombocytopenia and anemia caused by a persistent high linezolid concentration in patients with renal dysfunction. J Infect Chemother 2011;17:70-75.
  4. Pea F, et al. Linezolid disposition after standard dosages in critically ill patients undergoing continuous venovenous hemofiltration: A report of 2 cases. Am J Kidney Dis 2004; 44:1097-1102.
  5. Pea F, et al. Hyperlactacidemia potentially due to linezolid overexposure in a liver transplant recipient. Clin Infect Dis 2006;42:434-435.
  6. Bosso JA, et al. Linezolid pharmacokinetics in adult patients with cystic fibrosis. Antimicrob Agents Chemother 2004;48: 281-284.
  7. Hallam MJ, et al. Potential subtherapeutic linezolid and meropenem antibiotic concentrations in a patient with severe burns and sepsis. J Burn Care Res 2010;31:207-209.