Pharmacokinetics and Elimination Efficiency of Linezolid during Dialysis

Abstract

Linezolid (LZD) is an option for treating infections caused by multi-resistant Gram-positive bacteria. The protein-binding rate of LZD markedly influences its elimination by dialysis, with limited data suggesting that LZD is cleared by intermittent hemodialysis. Here, we investigated the protein-binding rate and elimination efficiency of LZD in a sepsis patient receiving dialysis. The oral administration of LZD at 600 mg/day resulted in protein-binding and free rates of the drug of 20.4% and 79.6%, respectively, 24 h after administration. By comparing the LZD concentration before and after dialysis, the elimination efficiency of free LZD as a result of dialysis was found to be 40.6%. Our sepsis patient showed higher plasma concentrations of LZD at trough after hemodialysis than the reported concentrations in normal renal function patients. However, it is not clear from our present findings if a relationship exists between myelosuppression and plasma LZD concentration.

• concentration
• dialysis
• linezolid
• myelosuppression
• protein binding rate

INTRODUCTION

Linezolid (LZD) is a synthetic oxazolidinone antimicrobial agent with a unique mechanism of action compared with existing agents.^1,2 LZD has proven effective for the treatment of infections caused by multidrug resistant Gram-positive cocci, including vancomycin-resistant strains of Staphylococcus aureus and Enterococci, and penicillin-resistant Streptococcus pneumoniae, which are resistant to most current antimicrobial therapies.^3–5 Following oral administration, LZD is fully bioavailable and has a volume distribution that is approximately equivalent to total body water.⁴ In addition, plasma concentrations of LZD in elderly and those in patients with mild to moderate hepatic impairment or mild to severe renal impairment are similar to those found in young or healthy individuals.⁵ However, our group has detected high trough concentrations of LZD in patients with renal dysfunction, suggesting that the impairment of LZD elimination may be a factor in the development of thrombocytopenia.^6–9 To date, however, no studies have examined the relationship between blood LZD levels and the development of myelosuppression.

Here, we investigated the elimination efficiency and pharmacokinetics (PK) of LZD in a hemodialysis patient with infectious sepsis caused by methicillin-resistant S. aureus (MRSA) who was administered LZD immediately prior to dialysis.

CASE REPORT

A 77-year-old Japanese woman on hemodialysis was admitted to our hospital on suspicion of infection at the site of lower extremity amputation. Meropenem hydrate was immediately administered after hospitalization. On day 35 of admission, the patient’s C-reactive protein (CRP) level was 8.8 mg/dL (normal, ≤0.2 mg/dL), white blood cell count (WBC) was 71 × 10⁹/L (normal, 3.5–8.5 × 10⁹/L), blood urea nitrogen (BUN) was 30.5 mg/dL (normal, 8–22 mg/dL), serum creatinine (SCr) was 4.19 mg/dL (normal, 0.40–0.70 mg/dL), aspartate aminotransferase (AST) was 10 IU/L (normal, 13–33 IU/L), and alanine aminotransferase (ALT) was 3 IU/L (normal, 8–42 IU/L). MRSA was detected by the culture of venous blood, confirming the diagnosis of sepsis. The patient was treated with a therapy of LZD starting on day 35. During her hospital stay, the patient tolerated hemodialysis three times per week for 3 h without complications. Elevated WBC was observed 2 days after initiating the LZD therapy. No changes in AST, ALT, BUN, or SCr during the LZD therapy were observed, and MRSA was not detected in venous blood cultures by day 13 after initiating therapy. Twenty-four hours after the oral administration of 600 mg/day LZD, the protein-binding and free rates of LZD were approximately 20.4% and 79.6%, respectively. In addition, the elimination efficiency of free LZD was approximately 40.6% during dialysis.

LZD Administration and Determination of Plasma Concentrations

The patient was orally administered LZD after breakfast at a dose of 600 mg every 24 h. On days when the patient received dialysis, LZD was administered just after the dialysis was completed. The patient was dialyzed using a perfusion flow rate of 500 mL/min, and the blood flow rate was maintained between 150 and 200 mL/min. Heparinized blood samples were collected on days 4, 9, and 14 immediately before (C1, C2, and C3, respectively) and 2 h after the hemodialysis sessions (C4) (Table 1). Plasma was immediately separated by centrifugation and ultrafiltrates were obtained using an Amicon Centrifree Micro-partition Unit (Millipore, County Cork, Ireland) and stored at –80°C until needed for analysis. Free LZD concentrations were measured by high-performance liquid chromatography (HPLC) using a CBM-20A system (Shimadzu Co., Kyoto, Japan) consisting of an LC-20AT flow pump and SPD-10AV VP ultraviolet (UV) detector (Shimadzu Co.), as previously described.¹⁰

Table 1.  Pharmacokinetics of linezolid after daily administration of a 600-mg oral dose.

	LZD concentration		Protein-binding	Biochemical data
	Serum (μg/mL)		ratio	CRP	BUN	Scr	AST	ALT	WBC	RBC	Hb	PLT
Sampling point	Free	Total	%	mg/dL	mg/dL	mg/dL	IU/L	IU/L	×10^2	×10^4	g/dL	×10^3
Day 4 (C1)	16.3	20.4	20.1	8.8	30.5	4.19	10	3	71	446	12.2	247
Day 9 (C2)	22.6	27.1	15.9	6.7	31.4	4.06	10	4	58	452	12.9	145
Day 14 (C3)	23.3	29.5	21.0	7.3	40.6	4.64	9	4	73	424	12.1	67
Day 14 (C4)	9.5	12.4	23.4	–	14.1	1.98	–	–	–	–	–	–

Notes: The concentration of linezolid immediately before (C1, C2, and C3) and 2 h after hemodialysis (C4) is shown. CRP, C-reactive protein; BUN, blood urea nitrogen; Scr, serum creatinine; AST, aspartate aminotransferase; ALT, alanine aminotransferase; WBC, white blood cell; RBC, red blood cell; Hb, hemoglobin;, PLT;, platelet.

The elimination efficiency of free LZD was calculated as the difference between the free concentrations of LZD at time points C3 and C4 (described above), using the following equation: (C3_free – C4_free)/C3_free, where “C3_free” and “C4_free” represent the free LZD concentrations of C3 and C4, respectively.

Ethics

The study protocol was approved by the ethics committee of the National Hospital Organization Kumamoto Medical Center. The study was conducted in accordance with the ethical guidelines of the Declaration of Helsinki and the guidelines of the International Conference on Harmonization Good Clinical Practice.^11,12

DISCUSSION

We investigated the protein-binding rate, elimination efficiency, and accumulation of LZD after repetitive administration in a hemodialysis patient treated for infectious sepsis due to MRSA. Even though the elimination efficiency of free LZD as a result of dialysis was found to be 40.6%, the patient had increasing blood concentrations of LZD on repeated daily administration and also displayed decreasing platelet counts. Notably, although the patient showed a favorable response to treatment with LZD, she developed thrombocytopenia, which was thought to result from elevated serum LZD concentrations. Based on this case report, information on the protein-binding rate and elimination efficiency of LZD is important for patients undergoing hemodialysis, because the extraction ratio of LZD by dialysis is markedly affected by these two factors.

We previously proposed that the development of thrombocytopenia increases with elevated blood LZD concentrations.^7–9 Michael et al.¹³ reported that the dose of LZD does not need to be altered for patients with impaired renal function based solely on the results of a single-dose study, which demonstrated that approximately 37% of the drug was extracted as it passed through the dialyzer. However, Matsumoto et al.¹⁴ reported that in thrombocytopenic patients, increased LZD trough concentration and area under the plasma LZD concentration (AUC) were observed in patients with renal dysfunction, and suggested that higher drug exposure led to the development of thrombocytopenia. We have also previously observed increased LZD concentrations in patients with deteriorated renal function.⁹ In the present case, the plasma concentration of LZD increased with increasing treatment duration, and an inverse correlation between the patient’s PLT count and LZD concentration was detected. Taken together, these results show that the adverse effects of thrombocytopenia may have been due to LZD accumulation associated with the delayed elimination of LZD.

The underlying mechanisms of LZD-induced adverse effects relating to bone marrow inhibition remain unclear; however, LZD may cause the anemia that appears secondary to direct marrow suppression via the inhibition of mitochondrial respiration by a mechanism similar to that of chloramphenicol.¹⁵ Drug-induced immune thrombocytopenia falls into one of two categories: that caused by the quinine/quinidine drug class or heparin-induced thrombocytopenia (HIT).^16,17 Quinine/quinidine-induced thrombocytopenia involves the binding of the drug or metabolites to the platelet membrane glycoproteins 1b/IX or IIb/IIIa, with the resulting immunogenic complexes being bound by the Fab portion of immunoglobulin G (IgG).^16,17 The Fc portion of the bound IgG molecules is bound to macrophages, leading to the clearance of the complexes by the reticuloendothelial system.^18,19 HIT occurs after heparin-activated platelets release platelet factor 4 (PF4), forming heparin-IgG-PF4 complexes that are immunogenic for IgG molecules whose Fc portion binds to platelet FcγIIa receptors, resulting in clustering, which is a characteristic pathology of numerous autoimmune diseases, and further platelet activation.¹⁸ Paradoxically, thrombosis may occur secondary to the activation and clumping of the platelets. The mechanism of thrombocytopenia induced by LZD will be investigated in a future study.

In conclusion, LZD may potentially cause the reduction of PLT counts and development of anemia. Such adverse effects may possibly be due to the sustained elevation of LZD concentrations, as evidenced by our present findings in a sepsis patient who underwent hemodialysis and showed higher trough concentrations of LZD than those typically reported in normal renal function patients. Thus, care should be taken when prescribing LZD for renal failure and dialysis patients, because the reported incidence of LZD-induced bone marrow inhibition is sixfold greater in patients with terminal-stage kidney failure than in healthy subjects.¹⁹ Renal physicians should be aware of this potentially fatal adverse drug effect and the elimination efficiency rate of free LZD during dialysis.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.