Abstract
To the Editor:
Because the development of severe hypophosphatemia after discontinuation of linezolid has not been reported previously, the present case may stimulate study toward understanding the pathophysiologic mechanisms underlying severe hypophosphatemia in similar cases. This may be the first report of additional side effects after the withdrawal of linezolid, of which physicians must become aware because linezolid is being increasingly used in clinical practice.
A 75-year-old Japanese male with a diagnosis of sepsis was referred to our hospital after two weeks of hospitalization following a partial gastrectomy for gastric cancer. Physical examination revealed an alert, malnourished individual. His blood pressure was 94/60 mm Hg, pulse rate 84 beats/min, respiratory rate 26 breaths/min, and temperature 38.5°C. Neurological evaluation revealed paralysis of the lower extremities. The patient's serum creatinine, alanine aminotransferase (ALT), and bilirubin concentrations were normal, but his white blood cell (WBC) count was high (141.2×102/mcL) and his platelet count was low (6.9×104/mcL). His mineral concentrations, including his serum phosphate (2.6 mg/dL), were also within normal range, and his arterial blood gases were normal (pH, 7.495; PCO2, 33.0 mm Hg; PO2, 71.7 mm Hg) with the breathing of room air. Chest radiography showed no consolidation or pleural effusion. Magnetic resonance imaging (MRI) of the cervical spine revealed a diffuse, low-intensity area anteriorly around the C5/6 vertebrae, consistent with pyogenic spondylitis. Anterior spinal fusion and debridement were performed to drain an abscess on the second day after the patient's transfer. Blood cultures and abscess fluid grew methicillin-resistant Staphylococcus aureus (MRSA), and the patient was treated with linezolid (600 mg q/12h).
Seventy-two days after the first administration of linezolid, the patient developed dyspnea, hypothermia, and coma. Laboratory and radiologic assessment showed no sign of recurrent spinal infection or systemic infection, but arterial blood gas analysis revealed metabolic acidosis as follows: pH, 7.09; PaO2, 63 mmHg; PaCO2, 53 mmHg with breathing of O2 at 10L/min by mask, accompanied by a high lactic acid concentration (>25 mol/L) (Fig. 1). Given these data, linezolid-induced lactic acidosis was suspected, and vancomycin was substituted immediately for linezolid. The patient required mechanical ventilation because of respiratory failure with muscle hypotonia, and continuous hemodiafiltration for five days to normalize his blood pH and clear linezolid from his plasma. Although his blood lactic acid concentration returned to normal after this treatment, his blood phosphate concentration remained extremely low despite daily intravenous supplementation with monopotassium phosphate (10 mEq/day). After administration of enteral nutrition enriched with phosphate (88 mg/100 kCal), the patient's serum phosphate concentration gradually returned to normal. The patient was liberated from mechanical ventilation after 20 days of intensive care, and was discharged to a rehabilitation center free of infection, lactic acidosis, or hypophosphatemia.
Clinical course. CHDF=continuous hemodiafiltration; IP=serum phosphorus. Arrows indicate intravenous supplementation of monopotassium phosphate.
The present case is the first to be reported of life-threatening hypophosphatemia after the discontinuation of linezolid following 72 days of treatment. The use of linezolid has been associated with serious adverse effects, such as bone marrow suppression and thrombocytopenia, peripheral neuropathy, and muscle weakness, which are most likely the result of mitochondrial toxicity [4–6]. Nerve and muscle tissues, being highly dependent on oxidative metabolism, are susceptible to disorders associated with disrupted respiratory-chain activity. Mitochondrial dysfunction also causes lactic acidosis because pyruvic acid, rather than being used for the production of adenosine triphosphate with acetyl-coenzyme A, is used for anaerobic glycolysis.
We hypothesized that the hypophosphatemia in the present case might have been at least partly due to the discontinuation of linezolid. Although we cannot prove conclusively that hypophosphatemia is consequential to the increased phosphate consumption in glycolytic processes, the clinical course of the patient we describe is consistent with this hypothesis. Phosphate is a major component of proteins, phospholipids, and nucleotides. Proliferating cells take up phosphorus, resulting in severe hypophosphatemia if phosphorus is not repleted [7]. Increased consumption of phosphates by mitochondrial reactivation might have caused the severe hypophosphatemia in the patient described here [7,8]. Possibly also contributing to this patient's hypophosphatemia were hemofiltration to normalize blood pH and remove linezolid [9].
Hypophosphatemia may occur in as many as 2%–3% of hospitalized patients and in as many as 30% of patients admitted to ICUs. A number of potential mechanisms may explain hypophosphatemia, for which there are primarily three mechanisms: Decreased intestinal absorption, increased renal excretion, and internal redistribution of inorganic phosphate [10,11]. Linezolid is used increasingly in current clinical practice for treating infectious diseases caused by MRSA. Physicians should monitor blood phosphorus concentrations of patients receiving linezolid to avoid complications, particularly after linezolid is discontinued, and should treat hypophosphatemia aggressively if it develops.