Linezolid-Associated Triad of Acute Pancreatitis, Lactic Acidosis, and Hypoglycemia: A Rare Case Report and Literature Review

Introduction

Linezolid is an oxazolidinone-class antibiotic commonly prescribed for difficult-to-treat gram-positive infections such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus [1]. Short courses of linezolid are generally well tolerated, with mild adverse effects including nausea, headache, or diarrhea. In contrast, extended use has been associated with more severe outcomes, including hematologic abnormalities, neurologic complications, and bone marrow suppression [2–4]. Recent reports have described a rare triad of pancreatitis, hypoglycemia, and lactic acidosis associated with linezolid therapy [5–8]. This triad is an underrecognized and potentially fatal manifestation of linezolid-induced mitochondrial toxicity [5–8]. We present a case illustrating this uncommon presentation to emphasize the importance of clinical vigilance, particularly in patients at high risk.

Case Report

We report the case of a 59-year-old woman with a complex medical history that included cytomegalovirus colitis complicated by bowel perforation and massive lower gastrointestinal bleeding, requiring a total colectomy with end ileostomy. Her past medical history was also significant for hypertension, type 2 diabetes mellitus, atrial fibrillation, and end-stage renal disease (ESRD). She was started on peritoneal dialysis in April 2023, which was discontinued in December 2023, after which she transitioned to hemodialysis 3 times per week.

The patient was initially admitted with community-acquired pneumonia complicated by a loculated pleural effusion suggestive of empyema. Due to the nature of the effusion, thoracentesis was not feasible, and sputum samples could not be obtained. She showed clinical improvement with empirical intravenous (IV) antibiotics and was discharged on oral linezolid for a planned 4-week course.

Three weeks into therapy, on April 29, 2024, she presented to the emergency department with the sudden onset of severe epigastric pain rated 10/10, described as sharp and radiating to the back, and associated with nausea and vomiting. This was her first episode of pancreatitis.

On evaluation, her serum lipase level was markedly elevated (>1645 U/L), accompanied by elevated lactate levels (3–4 mmol/L) and relative hypoglycemia (glucose 2.8–3.9 mmol/L). Additional laboratory investigations revealed pancytopenia, including leukopenia (2.6×109/L), thrombocytopenia (38×109/L), and anemia (hemoglobin 58 g/L). Her BISAP score was calculated as 5, corresponding to an estimated mortality rate of approximately 22%.

Abdominal ultrasound and contrast-enhanced computed tomography (CT) of the abdomen with IV contrast ruled out gallstones, biliary obstruction, and mesenteric ischemia. The pancreas appeared grossly unremarkable. CT imaging also demonstrated stable mild wall thickening involving the left upper quadrant small bowel loops, the presence of free fluid, generalized subcutaneous soft tissue edema, progressive bilateral pleural effusions, and lower lobe compressive atelectasis with patchy airspace opacities.

Differential diagnoses considered included gallstone disease, alcohol-related pancreatitis, hypertriglyceridemia, ischemia, and drug-induced causes (isoniazid, statins). All were excluded based on clinical, biochemical, and imaging findings.

During hospitalization, linezolid was discontinued upon admission. Application of the Naranjo probability scale yielded a score of 5, indicating a probable adverse drug reaction. Isoniazid (initiated 5 months earlier for latent tuberculosis) was also withheld. The patient was treated conservatively with IV fluid resuscitation using normal saline at 1.5 mL/kg/h, while closely monitoring for signs of fluid overload given her dialysis dependence. Pain was controlled with acetaminophen and oral tramadol 50 mg twice daily. Empirical ceftriaxone was escalated to piperacillin-tazobactam for a possible chest infection. All other home medications were continued as appropriate. Her home medications prior to admission are summarized in Table 1.

Over the next few days, her symptoms improved markedly. Abdominal pain resolved, oral intake was resumed, lactate levels normalized, and her platelet count began to recover. She remained hospitalized for social reasons and was discharged home 2 weeks later in stable condition.

Discussion

Linezolid undergoes non-enzymatic oxidation to 2 inactive metabolites – hydroxyethyl glycine and aminoethoxyacetic acid – that are cleared through both the renal and non-renal pathways, with higher metabolite levels reported in cases of severe renal impairment [1]. In individuals with reduced kidney function, this accumulation could increase overall exposure and contribute to adverse effects. In our patient with ESRD), diminished clearance might have played a role in the observed presentation [1]. Although chronic renal failure and hemodialysis are recognized risk factors for pancreatitis, linezolid-associated pancreatitis has been described in patients without renal dysfunction, suggesting that a mitochondrial toxic effect could be directly involved and may be amplified – but not entirely explained – by renal impairment [6].

To the best of our knowledge, only 4 similar cases of the triad of hypoglycemia, lactic acidosis, and acute pancreatitis have been reported to date, making the present case the fifth [5–8]. Johnson et al (United States) described a 34-year-old man with ESRD and vancomycin-resistant Enterococcus tricuspid endocarditis treated with linezolid 600 mg IV every 12 hours who, on day 11, developed this triad and improved rapidly after linezolid withdrawal and a switch to daptomycin [8]. Tobias et al reported a 52-year-old woman receiving linezolid 600 mg twice daily plus ertapenem for an intra-abdominal abscess who developed the triad after 6 weeks of therapy and improved after discontinuation of linezolid, hemodialysis, IV thiamine, dextrose, and supportive fluids [5]. Kim et al (Qatar) detailed the case of a 68-year-old man with chronic kidney disease treated with oral linezolid 600 mg (planned 6-week course) plus IV cefepime for diabetic foot osteomyelitis, with cultures growing Enterococcus faecium, Pseudomonas aeruginosa, and Escherichia coli, who developed the triad (with relative hypoglycemia) after about 5 weeks of therapy, improved within days after discontinuation of linezolid and supportive care, but died 6 months later from septic shock due to hospital-acquired infections and progression of kidney disease [7]. Santos-Vazquez et al (Mexico) described a 41-year-old woman treated with oral linezolid 600 mg once daily for a gluteal filler–related soft tissue infection due to Mycobacterium abscessus and Proteus mirabilis, who developed the triad after 3 weeks of therapy and rapidly progressed to multiorgan failure, dying 24 hours after intensive care unit (ICU) admission [6]. The fifth case is the present report.

Hypoglycemia generally occurs within 1 to 4 weeks of treatment and typically resolves following drug discontinuation, although persistence beyond 24 hours has been reported [6]. Mechanistically, linezolid inhibits monoamine oxidase, thereby altering catecholamine metabolism, while mitochondrial dysfunction in pancreatic β-cells impairs insulin secretion and disrupts glucose homeostasis [6].

Pancreatitis in the context of linezolid toxicity is rare but has been documented [5–8]. The underlying mechanisms are not fully understood but may involve mitochondrial dysfunction leading to microvascular compromise and pancreatic tissue injury [7, 8]. Direct acinar cell toxicity has also been suggested [7]. Moreover, mitochondrial impairment can affect pancreatic β-cell function and insulin regulation, thereby contributing to hypoglycemia [8]. Regarding the route of administration, most reported cases of pancreatitis – including ours – have involved oral linezolid. Nevertheless, given its nearly 100% bioavailability, a meaningful pharmacokinetic difference between oral and IV administration is unlikely [9]. The observed toxicity may likely reflect a systemic, class-related effect rather than one determined by the route of administration.

Therapeutic drug monitoring of linezolid is recommended to maintain plasma concentrations within 2 to 8 mg/L to ensure therapeutic efficacy while minimizing adverse effects [10]. This is particularly important in vulnerable populations, including patients with renal or hepatic impairment, older adults, critically ill individuals, and those receiving concomitant medications that may alter drug metabolism [10]. However, therapeutic drug monitoring of linezolid was not available at our center.

Management of suspected linezolid toxicity begins with prompt discontinuation of the drug. In reported cases, supportive strategies such as thiamine supplementation and hemodialysis have been shown to reduce lactic acid levels and facilitate recovery [11].

In our patient, cessation of linezolid and supportive management led to complete resolution of clinical symptoms and biochemical abnormalities. The Naranjo probability scale yielded a score of 5, consistent with a probable adverse drug reaction. The close temporal association with prolonged linezolid exposure, exclusion of alternative etiologies, and resolution after drug withdrawal collectively support the diagnosis.

Conclusions

Although linezolid toxicity is rare, linezolid has been associated with a serious triad of acute pancreatitis, lactic acidosis, and hypoglycemia, particularly in patients with underlying renal dysfunction. Clinicians should remain vigilant for this potential complication and maintain a high index of suspicion in symptomatic patients receiving prolonged therapy. Early recognition and prompt discontinuation are essential, as illustrated by our patient’s rapid clinical and biochemical recovery following drug cessation, which strongly supported a probable adverse drug reaction.