Oxazolidinones

General adverse effects and adverse reactions

Linezolid is generally well tolerated [ ]. The most frequently reported adverse events were diarrhea, headache, nausea and vomiting, insomnia, constipation, rash, and dizziness. Thrombocytopenia was also documented in few patients (about 2%). In a phase II, open, multicenter study of intravenous linezolid followed by oral linezolid suspension, both in a dose of 10 mg/kg every 12 hours in 66 children, the most common adverse reactions were diarrhea (10%), neutropenia (6.4%), and raised alanine aminotransferase activity (6.4%) [ ].

In children the common adverse events have been similar to those found in adults, although thrombocytopenia has not been as common [ ].

Observational studies

In a prospective, multicenter, open, non-comparative, non-randomized trial In patients with serious Gram positive infections, who received linezolid 600 mg bd, the overall adverse event rate was 18%. The most common adverse reactions were increased liver function tests, rash, and gastrointestinal disturbances. Three patients required withdrawal of therapy for rash, one for raised liver function tests, and one for thrombocytopenia [ ].

In a retrospective analysis in 44 patients taking linezolid (mean duration 29; range 8–185 days), the clinical cure rate was 73%; 28 had adverse reactions (thrombocytopenia, n = 13; anemia, n = 7; gastrointestinal, n = 12; peripheral neuropathy, n = 1; serotonin syndrome, n = 1) [ ].

In a retrospective analysis in 20 patients receiving linezolid for orthopedic infections, eight developed reversible myelosuppression, one had irreversible peripheral neuropathy, and two withdrew because of pancytopenia or urticaria [ ].

In a retrospective analysis in 42 patients receiving linezolid for osteomyelitis, the clinical cure rate was 55% in the 20 patients who received therapy for at least 6 weeks. Adverse events included gastrointestinal disturbances (15%), thrombocytopenia (10%), anemia (10%), neutropenia (5%), and rash (5%) [ ].

There were serious adverse events in 18 of 24 patients with mycobacterial infection treated with combinations that included linezolid [ ]. There was an optic and/or peripheral neuropathy in 11 cases and anemia in 10 cases.

Cardiovascular

In a placebo-controlled, crossover study in 12 healthy men who took one oral dose of linezolid 600 mg or a placebo tablet followed by an intravenous tyramine pressor test until the systolic blood pressure increased by at least 30 mmHg above baseline, there was a significant difference in the pressor response to intravenous tyramine between linezolid and placebo [ ].

Severe bradycardia with an increased blood pressure has been attributed to linezolid [ ].

• A 49-year-old woman with cancer of the biliary tree developed a fever and jaundice. Dilatation of the right biliary tract was confirmed by ultrasound and nuclear magnetic resonance. She was given ceftazidime 4 g/day and oral linezolid 600 mg/day. Unexpectedly, 2 days later her blood pressure rose to 170/90 mmHg and was associated with severe bradycardia 37–40/minute. Linezolid was withdrawn. The pulse rate became normal after 48 hours and the blood pressure fell.

The mechanism underlying this effect is unknown, but it may have been related to the fact that linezolid is a monoamine oxidase inhibitor.

Nervous and sensory systems

Long-term use of linezolid can be associated with severe peripheral and optic neuropathy. Eight patients with multidrug-resistant tuberculosis were treated with linezolid 600 mg/day plus at least four other drugs [ ]. Cultures became negative in all patients in an average of 82 days. Four patients developed a peripheral neuropathy, two developed an optic neuropathy, and one developed anemia. Although the optic neuropathy resolved after withdrawal of linezolid the peripheral neuropathy persisted. Three patients stopped taking linezolid after 7–9 months, two because of adverse effects and one for economic reasons.

There have been several reports of optic and peripheral neuropathies [ , ].

• Peripheral and optic neuropathy occurred in a 76-year-old man after he had taken linezolid for about 6 months [ ].

• A 65-year-old man who had taken linezolid 600 mg bd for 1 year because of an infection with a multidrug-resistant Staphylococcus aureus (MRSA) developed bilateral gradual loss of vision over 2 months. Linezolid was withdrawn and his visual acuities returned to normal over 15 months.

• A 40-year-old monocular woman with pyoderma gangrenosum who was taking long-term corticosteroids developed progressive, painless, loss of central vision in her remaining eye over 2 weeks after taking ciprofloxacin and linezolid 600 mg bd for recurrent meticillin-resistant Staphylococcus aureus (MRSA) infections for 6 months. At the same time she developed distal numbness and paresthesia. Linezolid was withdrawn and 1 month later her color vision had improved to 8/14. Four months later, there was 70% subjective improvement, a visual acuity of 20/40, normalization of the visual field, and mild nerve pallor. The peripheral numbness and tingling did not improve. Normal vision persisted 18 months later.

• A 66-year-old man developed progressive, painless, bilateral loss of vision and peripheral numbness after taking rifampicin and linezolid 600 mg bd for 5 months. Both drugs were withdrawn and 3 months later his visual acuity was 20/25 in the right eye and 20/20 in the left and there was resolution of the disc edema. The peripheral numbness persisted.

• A 79-year-old woman developed progressive, painless loss of vision, more in the left eye than the right over 1 month after taking linezolid for 10 months. There was also an axonal neuropathy, which was attributed to linezolid, which was withdrawn. Three months later, she reported subjective visual improvement, and the acuity in the left eye was 20/50. However, the acuity in the right amblyopic eye was unchanged. Six months later, the acuity in the left eye was 20/30. Color vision and Goldmann visual field improved. The neuropathy was unchanged. In most cases, optic neuropathies resolved after stopping linezolid but peripheral neuropathies did not; the duration of therapy seems to be the most important factor [ ].

• A 46-year-old white woman developed a severe, painful peripheral neuropathy while taking oral linezolid 600 mg bd for 6 months [ ]. Nerve conduction studies showed a sensorimotor axonal neuropathy. Extensive assessment did not show alternative explanations for her neuropathy. When she died 1 month after withdrawal of linezolid, the neuropathy had not resolved.

• A 27-year-old white woman took linezolid 600 mg bd for 6 months and developed paresthesia in her extremities, numbness of the legs below the knee, and intermittent sharp pain in both feet [ ]. There was peripheral sensory loss in the “glove and stocking” distribution. Nerve conduction studies showed sensory motor axonal neuropathy. Linezolid was withdrawn and 5 months later she reported no pain. However, nerve conduction studies showed that the peripheral neuropathy persisted. Other cases of linezolid-induced peripheral neurotoxicity have been reported [ , ].

• A 70-year-old man took linezolid for 10–12 days and complained of numbness in his toes. Nerve conduction studies showed sensory motor axonal damage. During the next 5 months he develop progressive perineal anesthesia without fecal incontinence or urinary tract disorder. Spinal cord MRI and nerve biopsy were normal. The hemoglobin was 8.5 g/dl. Linezolid was withdrawn after 24 weeks of therapy. The perineal anesthesia disappeared after 8 months, but the neuropathy persisted.

• A 45-year-old woman complained of bilateral, predominantly left-sided paresthesia of the toes after taking linezolid for 6 months. One week later, linezolid was withdrawn because of a glove-and-stocking neuropathy without abnormal ankle reflexes. Nerve conduction studies were compatible with a sensory axonal neuropathy. Two weeks after withdrawal of linezolid, she reported subjective improvement of the sensory perception. After 3 months minor bilateral paresthesia persisted.

• A 38-year-old man presented with bilateral isolated lower limb dysesthesia after taking linezolid for 2 months. Linezolid was withdrawn and voriconazole was continued while the neurological signs improved. Spinal MRI and lumbar puncture were normal; a search for antineuronal antibodies in serum and CSF was negative. After 6 months the paresthesia persisted.

• A 42-year-old woman developed a severe irreversible sensory polyneuropathy after a 6-month course of linezolid.

• Bell’s palsy has been reported in a 49-year-old man after 3 weeks of linezolid therapy; the symptoms recurred after rechallenge [ ].

• Posterior reversible leukoencephalopathy has been described a 71-year-old woman after 5 days of intravenous linezolid therapy; she improved rapidly after withdrawal of linezolid [ ].

Prolonged use of linezolid can cause a painful neuropathy [ ].

• A 53-year-old woman developed a pure small-fiber painful neuropathy after taking linezolid for 6 months. Eight months after withdrawal of linezolid her skin became fully reinervated, the neuropathic pain resolved, and the warm threshold normalized.

This raises the possibility that small-diameter sensory nerves in the skin, which are responsible for transmitting nociceptive information, might be affected by linezolid.

Sensory systems

Two patients undergoing long-term treatment (both 11 months) with linezolid for pneumonia had reduced visual acuity, dyschromatopsia, and cecocentral scotomata characteristic of toxic optic neuropathy [ ]. Visual function slowly recovered 3–4 months after withdrawal of linezolid.

• A 56-year-old man developed a toxic optic neuropathy after long-term treatment with linezolid 600 mg bd for 12 months then 600 mg/day for 44 months [ ]. Linezolid was withdrawn and he noted subjective visual improvement within several weeks.

• A 27-year-old woman developed an optic and peripheral neuropathy after taking linezolid for 154 days for osteomyelitis [ ]. A glucocorticoid exacerbated the visual loss. Withdrawal of linezolid resulted in marked improvement.

Long-term use of linezolid can be associated with severe peripheral and optic neuropathy (swollen or pale optic disc), symmetrical painless impairment of visual acuity and color vision, and bilateral visual field defects [ ].

Of 51 consecutive adults taking linezolid, one developed a reversible optic and an irreversible peripheral neuropathy after 24 months [ ].

Metabolism

Hyperlactatemia and metabolic acidosis are adverse effects of linezolid that could be related to impaired mitochondrial function.

• Linezolid-induced lactic acidosis occurred in a 70-year-old man during the first 7 days of treatment with linezolid [ ]. Mitochondria were studied from three patients, in whom weakness and hyperlactatemia developed during therapy with linezolid [ ]. The results suggested that linezolid interferes with mitochondrial protein synthesis, probably because of similarities between bacterial and mitochondrial ribosomes.

• Linezolid induced hyperlactatemia occurred in a 59-year-old patient during treatment with linezolid after liver transplantation [ ].

• A 63-year-old woman developed an optic neuropathy, encephalopathy, skeletal myopathy, lactic acidosis, and renal failure after taking linezolid for 4 months [ ]. Mitochondrial respiratory chain enzyme activity was reduced in affected tissues, without ultrastructural mitochondrial abnormalities and without mutations or depletion of mtDNA. In experimental animals, linezolid caused a dose- and time-related reduction in the activity of respiratory chain complexes containing mtDNA-encoded subunits and reduced the amount of protein in these complexes, whereas the amount of mtDNA was normal.

These results provide direct evidence that linezolid inhibits mitochondrial protein synthesis, with potentially severe clinical consequences.

Lactic acidosis has been associated with linezolid in an 80-year-old woman [ ] and in another patient after renal transplantation [ ].

Hematologic

Linezolid has been associated with myelosuppression, including anemia, leukopenia, pancytopenia, and thrombocytopenia. It is recommended that complete blood counts be monitored weekly in patients who take linezolid, especially those who take it for more than 2 weeks [ , , ]. It is recommended that complete blood counts be monitored weekly in patients who take linezolid, especially those who take it for more than 2 weeks. In children, thrombocytopenia is less common; however, the complete blood count should be monitored weekly while they are taking linezolid.

The mechanism of the anemia has been described and is thought to be inhibition of mitochondrial respiration. It can be managed relatively easily with transfusions. The thrombocytopenia is progressive and may require drug withdrawal; a mechanism for this effect has not been described. A bone marrow biopsy in a patient who developed thrombocytopenia 7 days after starting to take linezolid showed adequate numbers of normal-looking megakaryocytes. This finding alone argues against marrow suppression and supports an immune-mediated mechanism of platelet destruction [ ].

Reversible myelosuppression [ ] appears to be related to the duration of therapy, with a higher risk after more than 2 consecutive weeks of treatment [ ]. Myelosuppression with red cell hypoplasia has been reported in three patients taking linezolid 600 mg bd. The bone marrow changes were similar to those seen in reversible chloramphenicol toxicity. Another patient had sideroblastic anemia after taking linezolid for 2 months [ , ].

• Red cell hypoplasia and thrombocytopenia occurred in a 66-year-old man who took linezolid 600 mg bd [ ].

• Reversible pure red blood cell aplasia occurred in a 52-year-old black man who had taken linezolid for 8 weeks [ ].

Pancytopenia occurred in two patients taking linezolid 600 mg bd [ ].

In 19 patients there was thrombocytopenia in six of those who had taken it for more than 10 days; gastrointestinal bleeding was observed in one patient and four required platelet transfusions [ ]. Of 71 patients who took linezolid for 1–44 days, 48 took it for more than 5 days; among those 48, thrombocytopenia, with a 32–89% reduction in platelet count, occurred in 23; the platelet count fell to below 100 × 109/l in nine [ ].

In a retrospective study patients taking linezolid with lower pre-treatment hematological values were at greater risk not only of anemia but also thrombocytopenia [ ].

In a retrospective case-control study of linezolid in 91 patients with end-stage renal disease, 28 of whom were receiving hemodialysis, and patients with non-end-stage renal disease, severe thrombocytopenia and anemia were significantly more frequent in the former: 79% versus 43 and 71% versus 37 respectively [ ]. Survival analysis for the development of thrombocytopenia or death showed significant differences between the two groups.

In children, thrombocytopenia is less common; however, the complete blood count should be monitored weekly while children are taking linezolid. Vitamin B ₆ 50 mg/day may prevent or modify the course of linezolid-associated cytopenias. Two patients developed dyserythropoietic anemia, strikingly similar to chloramphenicol-associated myelotoxicity, after taking linezolid for 25–28 days [ ].

In a randomized, controlled, open, multicenter study in 430 patients with suspected or proven Gram-positive infections, patients received oral linezolid 600 mg every 12 hours or intravenous or intramuscular teicoplanin for up to 28 days [ ]. Five patients who were treated with linezolid had hematological adverse effects rated as moderate or severe, including hemolysis, anemia, leukopenia, and thrombocytopenia.

Hematological disturbances are a major concern when linezolid is administered for prolonged periods of time. Thrombocytopenia and anemia occurred in five of 51 adults taking linezolid, necessitating withdrawal in three of them [ ]. In contrast, in a retrospective chart review of the use of linezolid in 45 patients with marked baseline thrombocytopenia, although platelet counts fell in 35 patients during linezolid therapy, there was only one episode of non-life-threatening bleeding, which could have been attributable to coagulopathy from heparin therapy [ ].

The effects of pyridoxine, rifampicin, and renal function on hematological adverse events induced by linezolid have been studied in 52 patients [ ]. Thrombocytopenia was defined as a reduction to less than 75% of the baseline platelet count and anemia when the hemoglobin count fell by at least 0.2 g/dl from the baseline value. Linezolid alone was used in 24 patients and linezolid plus pyridoxine 200 mg/day in 28; pyridoxine did not prevent linezolid-related hematological adverse events (the cumulative probabilities of thrombocytopenia and anemia). Hematological adverse events were less frequent in patients taking rifampicin and were more frequent in patients with renal failure. Rifampicin was the only independent predictor associated with a lower risk of thrombocytopenia (HR = 0.37; 95% CI = 0.14, 0.98).

Sideroblastic anemia following prolonged linezolid therapy has been described in a patient with laryngeal cancer [ ].

Pancytopenia has been reported in two organ-transplant patients after treatment with linezolid 600 mg bd for 3 and 5 weeks [ ].