Linezolid use and drug-induced liver injury

Abstract

Linezolid is a frequently prescribed antibiotic for chronic infection suppression, such as in prosthetic joint infections. While well tolerated, its prolonged use can increase the risk of rare and serious side effects. We present a case of linezolid toxicity presenting with a constellation of adverse effects including bone marrow suppression, lactic acidosis, and drug-induced liver injury. Our case highlights the increased risk of acute multiorgan failure in patients using the antibiotic for extended durations, notably those with preexisting comorbidities.

Prosthetic joint infections are often colonized by multidrug-resistant bacteria, requiring prolonged use of antibiotics for infection suppression. Due to its excellent oral bioavailability and wide spectrum of action, linezolid is frequently prescribed in this patient population. While linezolid is well tolerated, patients often describe mild gastrointestinal side effects. More serious side effects including bone marrow suppression, lactic acidosis, liver dysfunction, and peripheral neuropathy occur infrequently. As prolonged use is recommended for prosthetic joint infections, it is imperative that physicians remain vigilant to these rarer side effects. We present an unusual case of linezolid toxicity presenting as multiorgan failure with a rare constellation of adverse effects including bone marrow suppression, lactic acidosis, and drug-induced liver injury.

CASE REPORT

An 82-year-old woman with known heart failure presented to the emergency department with a 1-week history of abdominal pain, nausea, and general malaise. She had recurrent prosthetic joint infection of the right knee with persistent colonization with Corynebacterium striatum. Chronic suppressive therapy with linezolid had been initiated 1 month prior to admission. On presentation, she was alert, oriented, and stable. Laboratory studies on admission are shown in Table 1. Computed tomography of the abdomen and pelvis showed increased diffuse low attenuation of the liver representing hepatic steatosis or hepatitis. A trial of diuresis was initiated, but lactate continued to rise, with worsening of thrombocytopenia and deteriorating synthetic liver function. Screening for viral hepatitis was negative and a disseminated intravascular coagulation workup including Coombs’ test, fibrinogen, and haptoglobin was unremarkable. A peripheral smear showed no evidence of hemolysis.

Table 1.

Laboratory results

Test	Reference range (male adults)	Day 1	Day 2a	Day 3	Day 9
Hemoglobin (g/dL)	12.3–16.6	7.2	6.9	9.1	8.4
White cell count (× 109/L)	3.4–9.6	3.9	4.7	9.4	9.4
Platelet count (× 109/L)	135–317	101	74	49	129
Lactate (mmol/L)	0.5–2.2	3.3	5.9	3.4	2.0
Alanine transaminase (U/L)	7–45	231	237	224	68
Aspartate transaminase (U/L)	8–43	280	293	233	27
Alkaline phosphatase (U/L)	35–104	188	171	162	170
International normalized ratio	0.9–1.1	2.2	2.2	2.3	1.8
Creatinine (mg/dL)	0.74–1.35b	1.65	1.7	1.7	1.29
Total bilirubin (mg/dL)	<1.2	1.3	3.6	2.2	0.8

^aLinezolid discontinued on day 2.

^bPatient’s baseline creatinine was 0.8 mg/dL.

The combination of liver injury and pancytopenia raised concern for linezolid toxicity. The agent was withdrawn and vancomycin was started. Within 24 hours, transaminases and lactate levels started decreasing. The hepatitis and lactic acidosis resolved over the course of 3 days, and markers of myelosuppression improved slowly (Table 1). The patient was discharged on day 9 of hospitalization. Vancomycin was transitioned to dalbavancin once every 2 weeks after discharge.

DISCUSSION

Few cases of linezolid-induced lactic acidosis or severe drug-induced liver injury have been documented; therefore, these side effects may not be widely appreciated. Of the cases reported, most patients had used the antibiotic for a longer duration.^1–3 These side effects of linezolid are therefore thought to be duration dependent, and it is recommended to limit its use to <28 days.⁴ Mitochondrial dysfunction is the proposed mechanism responsible for linezolid-induced lactic acidosis as well as the hepatic steatosis, which is related to severe impairment of the mitochondrial B oxidation of fatty acids.³

Our patient’s time course of clinical deterioration with liver dysfunction and concomitant lactic acidosis (onset after 4 weeks of linezolid) and the dramatic resolution following drug cessation corresponds to that of previous case reports of patients developing linezolid-induced lactic acidosis. A broad range of alternative causes of liver injury were ruled out. As therapy with linezolid has mostly been associated with mild transaminitis, and most cases of lactic acidosis occurred after 28 days of use, there are no current guidelines to monitor these parameters.

Our case presentation highlights the increased risk of acute multiorgan failure in patients using the antibiotic for extended durations, notably those with preexisting comorbidities. It also emphasizes the possibility of rapid reversal of the condition on discontinuation of the antibiotic. Therefore, physicians treating infections requiring prolonged linezolid use should be aware of these duration-dependent life-threatening adverse effects, and additional monitoring parameters should be considered.