IJGG Journal

Introduction

5-oxoproline intoxication is a rare and often iatrogenic cause of a high-anion gap metabolic acidosis [1]. The most common cause is the combined use of high dose flucloxacillin with acetaminophen. Current treatment primarily involves discontinuation of provoking agents and administering intravenous bicarbonate. However, N-acetylcysteine – a precursor for glutathione – may represent a promising supplementary treatment option. Here we present a case of 5-oxoproline intoxication induced by the concurrent use of flucloxacillin and acetaminophen for a prosthetic joint infection. Upon diagnosis of 5-oxoproline intoxication, discontinuation of provocative agents and administration of intravenous bicarbonate was started, however without improvement of the metabolic acidosis. Promptly, N-acetylcysteine was administered, resulting in noticeable improvement in the metabolic acidosis.

Case presentation

A 72-year-old man with a history of primary myelofibrosis and arthroplasty of the right knee, presented at the emergency department with malaise, lower back pain and redness, swelling and pain of the right knee. Laboratory tests revealed a C-reactive protein level of 172 mg/L (normal range <10mg/L). A prosthetic joint infection was suspected and ceftriaxone 2 grams daily was started intravenously. The knee joint was surgically treated with debridement, antibiotics and implant retention (DAIR). Acetaminophen was prescribed in the dose of 1000mg four times daily, ibuprofen 200mg three times daily and oxycodone extended release 20mg twice daily for pain management.

The day following admission, meticillin-sensitive Staphylococcus aureus was isolated from blood and synovial fluid cultures. Antibiotic treatment was switched to intravenous flucloxacillin with a loading dose of 2 grams followed by 12 grams per day continuously. A positron emission tomography (PET) scan showed the prosthetic joint infection of the knee and lumbar spondylodiscitis of L2 and L3, congruent with the lower back pain. Endocarditis could not be excluded. Therefore, flucloxacillin dose was maintained at 12 grams daily.

On the 24^th inpatient day, the patient developed dyspnea. Arterial blood gas analysis revealed a high anion gap metabolic acidosis with respiratory compensation (pH 7.31, pCO2 1.0kPa, bicarbonate 3.5mmol/L, base excess -20.3, albumin 17.4g/L). Additionally, the patient experienced acute kidney injury, with creatinine levels rising from 114 μmol/L to 232 μmol/L. We evaluated all possible causes of a high anion gap metabolic acidosis using the acronym ‘GOLDMARK’ and concluded that 5-oxoprolin intoxication, potentially aggravated by renal failure, was the cause. Urinary measurements confirmed our diagnosis, revealing elevated 5-oxoproline levels (Figure 1).

Acetaminophen and flucloxacillin were discontinued (cefazolin was started as alternative antibiotic treatment) and intravenous bicarbonate was administered both as bolus and continuously. This temporarily ameliorated the acid base balance. However, bicarbonate and base excess levels deteriorated again, prompting the early initiation of intravenous N-acetylcysteine (Figure 1). Subsequently, pH levels improved and stabilized around 7.40. Despite correction of metabolic acidosis, the patient’s condition further deteriorated due to progression of his underlying disease. Palliative sedation was initiated, and the patient passed away 12 days after the diagnosis of 5-oxoproline intoxication.

Figure 1: Course of urinary acetaminophen glucuronide, urinary 5-oxoproline, and serum bicarbonate levels, along with the corresponding times of intervention with sodium bicarbonate or N-acetylcysteine.

Discussion and conclusions

5-oxoproline intoxication is characterized by the accumulation of 5-oxoproline (also known as pyroglutamic acid), an intermediate in the gamma-glutamyl cycle [1]. The gamma-glutamyl cycle comprises a series of enzymatic reactions in which glutamate is combined with cysteine and glycine to form the tripeptide glutathione. Glutathione is subsequently broken down to form 5-oxoproline (Figure 2). Glutathione impedes the gamma-glutamyl cycle, and plays a crucial role in amino acid transport and the detoxification of reactive oxygen species [1].